chr7-155800141-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS1

The ENST00000430104.5(SHH):c.406G>A(p.Gly136Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000649 in 471,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

SHH
ENST00000430104.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.956

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: Benign. The variant received -15 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: 2.4697 (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.

BP4

Computational evidence support a benign effect (MetaRNN=0.004433453).

BP6

Variant 7-155800141-C-T is Benign according to our data. Variant chr7-155800141-C-T is described in ClinVar as Benign. ClinVar VariationId is 586571.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00158 (241/152348) while in subpopulation AFR AF = 0.00556 (231/41582). AF 95% confidence interval is 0.00497. There are 0 homozygotes in GnomAd4. There are 128 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHH	NM_000193.4 link	c.*2759G>A		3_prime_UTR_variant	Exon 3 of 3	ENST00000297261.7	NP_000184.1	Q15465

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHH	ENST00000297261.7 link	c.*2759G>A		3_prime_UTR_variant	Exon 3 of 3	1	NM_000193.4	ENSP00000297261.2		Q15465

Frequencies

GnomAD3 genomes

AF:

0.00158

AC:

241

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00557

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000325

AC:

AN:

150898

AF XY:

0.000260

show subpopulations

Gnomad AFR exome

AF:

0.00514

Gnomad AMR exome

AF:

0.000488

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000204

AC:

AN:

319242

Hom.:

Cov.:

AF XY:

0.000144

AC XY:

AN XY:

180304

show subpopulations

African (AFR)

AF:

0.00544

AC:

AN:

8634

American (AMR)

AF:

0.000476

AC:

AN:

27290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

10790

East Asian (EAS)

AF:

0.00

AC:

AN:

9216

South Asian (SAS)

AF:

0.00

AC:

AN:

59744

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27182

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2788

European-Non Finnish (NFE)

AF:

0.0000251

AC:

AN:

159134

Other (OTH)

AF:

0.0000691

AC:

AN:

14464

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00158

AC:

241

AN:

152348

Hom.:

Cov.:

AF XY:

0.00172

AC XY:

128

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.00556

AC:

231

AN:

41582

American (AMR)

AF:

0.000261

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00239

Hom.:

Bravo

AF:

0.00188

ExAC

AF:

0.000261

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 08, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.39

CADD

Benign

1.9

(source)

DANN

Benign

0.64

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.033

LIST_S2

Benign

0.31

MetaRNN

Benign

0.0044

MetaSVM

Uncertain

0.72

PhyloP100

-0.96

PROVEAN

Benign

-1.7

REVEL

Benign

0.16

Sift

Benign

0.39

Sift4G

Uncertain

0.042

Polyphen

0.013

MutPred

0.48

Gain of MoRF binding (P = 0.0141);

MVP

0.66

ClinPred

0.0020

GERP RS

-2.6

Mutation Taster

=100/0

polymorphism

(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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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