rs104894047

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000193.4(SHH):c.869G>A(p.Gly290Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,529,318 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0023 ( 7 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 18 hom. )

Consequence

SHH
NM_000193.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1U:1B:7

Conservation

PhyloP100: 0.804

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06371763).

BP6

Variant 7-155803420-C-T is Benign according to our data. Variant chr7-155803420-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 8887.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-155803420-C-T is described in Lovd as [Likely_benign]. Variant chr7-155803420-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00233 (354/152130) while in subpopulation EAS AF= 0.0343 (176/5134). AF 95% confidence interval is 0.0301. There are 7 homozygotes in gnomad4. There are 209 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 354 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHH	NM_000193.4 link	c.869G>A	p.Gly290Asp	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.869G>A	p.Gly290Asp	missense_variant	Exon 3 of 3	1	NM_000193.4	ENSP00000297261.2	Q15465
SHH	ENST00000430104.5 link	c.301+2876G>A		intron_variant	Intron 3 of 3	1		ENSP00000396621.1	C9JC48
SHH	ENST00000435425.1 link	n.302-2823G>A		intron_variant	Intron 3 of 4	1		ENSP00000413871.1	F8WEH4
SHH	ENST00000441114.5 link	n.302-2753G>A		intron_variant	Intron 3 of 4	1		ENSP00000410546.1	F8WB84

Frequencies

GnomAD3 genomes

AF:

0.00233

AC:

354

AN:

152020

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000748

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00374

Gnomad EAS

AF:

0.0342

Gnomad SAS

AF:

0.00393

Gnomad FIN

AF:

0.00897

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.00331

AC:

414

AN:

125120

Hom.:

AF XY:

0.00309

AC XY:

213

AN XY:

68864

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000415

Gnomad ASJ exome

AF:

0.00357

Gnomad EAS exome

AF:

0.0308

Gnomad SAS exome

AF:

0.00111

Gnomad FIN exome

AF:

0.00672

Gnomad NFE exome

AF:

0.000172

Gnomad OTH exome

AF:

0.00181

GnomAD4 exome

AF:

0.00112

AC:

1536

AN:

1377188

Hom.:

Cov.:

AF XY:

0.00108

AC XY:

737

AN XY:

679334

show subpopulations

Gnomad4 AFR exome

AF:

0.000132

Gnomad4 AMR exome

AF:

0.000113

Gnomad4 ASJ exome

AF:

0.00353

Gnomad4 EAS exome

AF:

0.0232

Gnomad4 SAS exome

AF:

0.00138

Gnomad4 FIN exome

AF:

0.00747

Gnomad4 NFE exome

AF:

0.000111

Gnomad4 OTH exome

AF:

0.00235

GnomAD4 genome

AF:

0.00233

AC:

354

AN:

152130

Hom.:

Cov.:

AF XY:

0.00281

AC XY:

209

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.000746

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00374

Gnomad4 EAS

AF:

0.0343

Gnomad4 SAS

AF:

0.00393

Gnomad4 FIN

AF:

0.00897

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.00118

Hom.:

Bravo

AF:

0.00174

ExAC

AF:

0.00114

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Uncertain:1Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Holoprosencephaly 3

Pathogenic:1Uncertain:1Benign:1

Aug 29, 2013

GeneReviews

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

- -

May 01, 2010

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:3

Jul 23, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 32939873, 31180159, 20425842, 18655123, 10556296, 19533790) -

Mar 05, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SHH: PP2, PP3, BS1, BS2 -

not specified

Benign:1

Oct 20, 2014

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Schizencephaly;C1840235:Solitary median maxillary central incisor syndrome;C1840529:Holoprosencephaly 3;C1968843:Microphthalmia, isolated, with coloboma 5

Benign:1

Dec 28, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

SHH-related disorder

Benign:1

Apr 25, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.080

CADD

Benign

8.7

DANN

Benign

0.77

DEOGEN2

Uncertain

0.67

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.53

MetaRNN

Benign

0.064

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.9

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.47

REVEL

Uncertain

0.59

Sift

Benign

0.21

Sift4G

Benign

0.27

Polyphen

0.55

Vest4

0.68

MVP

1.0

ClinPred

0.017

GERP RS

0.85

Varity_R

0.063

gMVP

0.70

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over