7-155803413-C-T

Position:

chr7-155803413-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The ENST00000297261.7(SHH):c.876G>A(p.Gly292=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000199 in 1,525,792 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0010 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

SHH
ENST00000297261.7 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 0.582

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 7-155803413-C-T is Benign according to our data. Variant chr7-155803413-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 65911.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=2, Uncertain_significance=1}.

BP7

Synonymous conserved (PhyloP=0.582 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00105 (159/152148) while in subpopulation AFR AF= 0.00359 (149/41556). AF 95% confidence interval is 0.00312. There are 1 homozygotes in gnomad4. There are 80 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 159 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SHH	NM_000193.4 linkuse as main transcript	c.876G>A	p.Gly292=	synonymous_variant	3/3	ENST00000297261.7	NP_000184.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
SHH	ENST00000297261.7 linkuse as main transcript	c.876G>A	p.Gly292=	synonymous_variant	3/3	1	NM_000193.4	ENSP00000297261	P1
SHH	ENST00000430104.5 linkuse as main transcript	c.301+2883G>A		intron_variant		1		ENSP00000396621
SHH	ENST00000435425.1 linkuse as main transcript	c.302-2816G>A		intron_variant, NMD_transcript_variant		1		ENSP00000413871
SHH	ENST00000441114.5 linkuse as main transcript	c.302-2746G>A		intron_variant, NMD_transcript_variant		1		ENSP00000410546

Frequencies

GnomAD3 genomes

AF:

0.00103

AC:

156

AN:

152036

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00352

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000206

AC:

AN:

121632

Hom.:

AF XY:

0.000149

AC XY:

AN XY:

66984

show subpopulations

Gnomad AFR exome

AF:

0.00430

Gnomad AMR exome

AF:

0.000168

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000222

Gnomad OTH exome

AF:

0.000266

GnomAD4 exome

AF:

0.000106

AC:

145

AN:

1373644

Hom.:

Cov.:

AF XY:

0.0000782

AC XY:

AN XY:

677512

show subpopulations

Gnomad4 AFR exome

AF:

0.00378

Gnomad4 AMR exome

AF:

0.000200

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000651

Gnomad4 OTH exome

AF:

0.000314

GnomAD4 genome

AF:

0.00105

AC:

159

AN:

152148

Hom.:

Cov.:

AF XY:

0.00108

AC XY:

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.00359

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000348

Hom.:

Bravo

AF:

0.00122

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 08, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 07, 2023	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 16, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Holoprosencephaly 3

Benign:2

Benign, no assertion criteria provided	curation	GeneReviews	Aug 29, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 22, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

2.5

DANN

Benign

0.82

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