7-155803142-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PP2PP3_Strong

The NM_000193.4(SHH):c.1147G>A(p.Ala383Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000565 in 1,416,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A383A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000047 ( 0 hom. )

Consequence

SHH
NM_000193.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:2U:7

Conservation

PhyloP100: 0.146

Publications

5 publications found

Variant links:

Genes affected

SHH (HGNC:10848): (sonic hedgehog signaling molecule) This gene encodes a protein that is instrumental in patterning the early embryo. It has been implicated as the key inductive signal in patterning of the ventral neural tube, the anterior-posterior limb axis, and the ventral somites. Of three human proteins showing sequence and functional similarity to the sonic hedgehog protein of Drosophila, this protein is the most similar. The protein is made as a precursor that is autocatalytically cleaved; the N-terminal portion is soluble and contains the signalling activity while the C-terminal portion is involved in precursor processing. More importantly, the C-terminal product covalently attaches a cholesterol moiety to the N-terminal product, restricting the N-terminal product to the cell surface and preventing it from freely diffusing throughout the developing embryo. Defects in this protein or in its signalling pathway are a cause of holoprosencephaly (HPE), a disorder in which the developing forebrain fails to correctly separate into right and left hemispheres. HPE is manifested by facial deformities. It is also thought that mutations in this gene or in its signalling pathway may be responsible for VACTERL syndrome, which is characterized by vertebral defects, anal atresia, tracheoesophageal fistula with esophageal atresia, radial and renal dysplasia, cardiac anomalies, and limb abnormalities. Additionally, mutations in a long range enhancer located approximately 1 megabase upstream of this gene disrupt limb patterning and can result in preaxial polydactyly. [provided by RefSeq, Jul 2008]

SHH Gene-Disease associations (from GenCC):

holoprosencephaly 3
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
microphthalmia, isolated, with coloboma 5
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia
polydactyly of a triphalangeal thumb
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
solitary median maxillary central incisor syndrome
Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: G2P, Ambry Genetics
skeletal system disorder
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
autosomal dominant preaxial polydactyly-upperback hypertrichosis syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hypoplastic tibiae-postaxial polydactyly syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
microphthalmia, isolated, with coloboma
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
syndactyly type 4
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
triphalangeal thumb-polysyndactyly syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
holoprosencephaly
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SHH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 26 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Gene score misZ: 2.9479 (below the threshold of 3.09). Trascript score misZ: 0.49525 (below the threshold of 3.09). GenCC associations: The gene is linked to polydactyly of a triphalangeal thumb, microphthalmia, isolated, with coloboma 5, solitary median maxillary central incisor syndrome, holoprosencephaly 3, skeletal system disorder, hypoplastic tibiae-postaxial polydactyly syndrome, holoprosencephaly, syndactyly type 4, microphthalmia, isolated, with coloboma, autosomal dominant preaxial polydactyly-upperback hypertrichosis syndrome, triphalangeal thumb-polysyndactyly syndrome.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.968

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHH	NM_000193.4 link	c.1147G>A	p.Ala383Thr	missense_variant	Exon 3 of 3	ENST00000297261.7	NP_000184.1	Q15465

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SHH	ENST00000297261.7 link	c.1147G>A	p.Ala383Thr	missense_variant	Exon 3 of 3	1	NM_000193.4	ENSP00000297261.2	Q15465
SHH	ENST00000430104.5 link	c.302-2897G>A		intron_variant	Intron 3 of 3	1		ENSP00000396621.1	C9JC48
SHH	ENST00000435425.1 link	n.302-2545G>A		intron_variant	Intron 3 of 4	1		ENSP00000413871.1	F8WEH4
SHH	ENST00000441114.5 link	n.302-2475G>A		intron_variant	Intron 3 of 4	1		ENSP00000410546.1	F8WB84

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151738

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000144

AC:

AN:

69260

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000535

GnomAD4 exome

AF:

0.00000474

AC:

AN:

1265246

Hom.:

Cov.:

AF XY:

0.00000483

AC XY:

AN XY:

620592

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25938

American (AMR)

AF:

0.00

AC:

AN:

21938

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21312

East Asian (EAS)

AF:

0.00

AC:

AN:

27148

South Asian (SAS)

AF:

0.00

AC:

AN:

60548

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38110

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4708

European-Non Finnish (NFE)

AF:

0.00000493

AC:

AN:

1013882

Other (OTH)

AF:

0.0000194

AC:

AN:

51662

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151738

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74122

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41402

American (AMR)

AF:

0.00

AC:

AN:

15214

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10438

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67902

Other (OTH)

AF:

0.00

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000141

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Holoprosencephaly 3

Pathogenic:2Uncertain:2

Mar 05, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 29, 2013

GeneReviews

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:curation

- -

Oct 01, 1997

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Sep 14, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SHH function (PMID: 15292211, 32939873). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SHH protein function. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 383 of the SHH protein (p.Ala383Thr). This variant is present in population databases (rs137853341, gnomAD no frequency). This missense change has been observed in individual(s) with holoprosencephaly (PMID: 9302262). This variant is also known as Ala384Thr. ClinVar contains an entry for this variant (Variation ID: 8886). -

Schizencephaly

Uncertain:2

Mar 05, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 29, 2020

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,PP3. -

Microphthalmia, isolated, with coloboma 5

Uncertain:1

Mar 05, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Solitary median maxillary central incisor syndrome

Uncertain:1

Mar 05, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Dec 18, 2019

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.16

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.83

Eigen

Benign

0.016

Eigen_PC

Benign

-0.036

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.65

M_CAP

Pathogenic

0.99

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.3

PhyloP100

0.15

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-1.0

REVEL

Pathogenic

0.73

Sift

Benign

0.34

Sift4G

Benign

0.35

Polyphen

0.87

Vest4

0.76

MutPred

0.85

Gain of glycosylation at A383 (P = 0.0346);

MVP

1.0

ClinPred

0.31

GERP RS

3.4

Varity_R

0.41

gMVP

0.54

Mutation Taster

=24/76

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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7-155803142-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over