chr7-155803719-C-T

Position:

chr7-155803719-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_000193.4(SHH):c.570G>A(p.Ser190=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00429 in 1,596,968 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0031 ( 7 hom., cov: 33)

Exomes 𝑓: 0.0044 ( 49 hom. )

Consequence

SHH
NM_000193.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -2.50

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.34).

BP6

Variant 7-155803719-C-T is Benign according to our data. Variant chr7-155803719-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 65877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-155803719-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-2.5 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00309 (471/152236) while in subpopulation SAS AF= 0.0178 (86/4822). AF 95% confidence interval is 0.0148. There are 7 homozygotes in gnomad4. There are 233 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 471 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHH	NM_000193.4 linkuse as main transcript	c.570G>A	p.Ser190=	synonymous_variant	3/3	ENST00000297261.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
SHH	ENST00000297261.7 linkuse as main transcript	c.570G>A	p.Ser190=	synonymous_variant	3/3	1	NM_000193.4	P1
SHH	ENST00000430104.5 linkuse as main transcript	c.301+2577G>A		intron_variant		1
SHH	ENST00000435425.1 linkuse as main transcript	c.301+2577G>A		intron_variant, NMD_transcript_variant		1
SHH	ENST00000441114.5 linkuse as main transcript	c.301+2577G>A		intron_variant, NMD_transcript_variant		1

Frequencies

GnomAD3 genomes

AF:

0.00310

AC:

471

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000917

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0178

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00435

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00510

AC:

1155

AN:

226548

Hom.:

AF XY:

0.00628

AC XY:

790

AN XY:

125708

show subpopulations

Gnomad AFR exome

AF:

0.000714

Gnomad AMR exome

AF:

0.00273

Gnomad ASJ exome

AF:

0.00103

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0185

Gnomad FIN exome

AF:

0.000261

Gnomad NFE exome

AF:

0.00425

Gnomad OTH exome

AF:

0.00638

GnomAD4 exome

AF:

0.00441

AC:

6376

AN:

1444732

Hom.:

Cov.:

AF XY:

0.00498

AC XY:

3583

AN XY:

719186

show subpopulations

Gnomad4 AFR exome

AF:

0.000927

Gnomad4 AMR exome

AF:

0.00262

Gnomad4 ASJ exome

AF:

0.00107

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0188

Gnomad4 FIN exome

AF:

0.000340

Gnomad4 NFE exome

AF:

0.00378

Gnomad4 OTH exome

AF:

0.00488

GnomAD4 genome

AF:

0.00309

AC:

471

AN:

152236

Hom.:

Cov.:

AF XY:

0.00313

AC XY:

233

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.000914

Gnomad4 AMR

AF:

0.00163

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0178

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00435

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00427

Hom.:

Bravo

AF:

0.00290

Asia WGS

AF:

0.00722

AC:

AN:

3478

EpiCase

AF:

0.00605

EpiControl

AF:

0.00689

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 17, 2014	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 19, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Holoprosencephaly 3

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -
Benign, no assertion criteria provided	curation	GeneReviews	Aug 29, 2013	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.34

CADD

Benign

9.6

DANN

Benign

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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