7-155812247-C-T

Variant names:

• chr7-155812247-C-T
• rs9333594
• NM_000193.4:c.-125G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000193.4(SHH):​c.-125G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0613 in 905,020 control chromosomes in the GnomAD database, including 1,968 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.076 (521 hom., cov: 32)
  • Exomes 𝑓: 0.058 (1447 hom.)
• Consequence: SHH NM_000193.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.06

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 7-155812247-C-T is Benign according to our data. Variant chr7-155812247-C-T is described in ClinVar as [Benign]. Clinvar id is 403436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-155812247-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.118 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHH	NM_000193.4	c.-125G>A		5_prime_UTR_variant	Exon 1 of 3	ENST00000297261.7	NP_000184.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHH	ENST00000297261.7	c.-125G>A		5_prime_UTR_variant	Exon 1 of 3	1	NM_000193.4	ENSP00000297261.2

Frequencies

GnomAD3 genomes AF: 0.0758 AC: 11540 AN: 152148 Hom.: 520 Cov.: 32

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0620

Gnomad ASJ AF: 0.0458

Gnomad EAS AF: 0.0177

Gnomad SAS AF: 0.0339

Gnomad FIN AF: 0.0877

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0594

Gnomad OTH AF: 0.0694

GnomAD4 exome AF: 0.0584 AC: 43978 AN: 752754 Hom.: 1447 Cov.: 10 AF XY: 0.0567 AC XY: 22445 AN XY: 395700

Gnomad4 AFR exome AF: 0.120

Gnomad4 AMR exome AF: 0.0667

Gnomad4 ASJ exome AF: 0.0493

Gnomad4 EAS exome AF: 0.0186

Gnomad4 SAS exome AF: 0.0373

Gnomad4 FIN exome AF: 0.0818

Gnomad4 NFE exome AF: 0.0590

Gnomad4 OTH exome AF: 0.0585

GnomAD4 genome AF: 0.0758 AC: 11544 AN: 152266 Hom.: 521 Cov.: 32 AF XY: 0.0762 AC XY: 5675 AN XY: 74464

Gnomad4 AFR AF: 0.121

Gnomad4 AMR AF: 0.0618

Gnomad4 ASJ AF: 0.0458

Gnomad4 EAS AF: 0.0178

Gnomad4 SAS AF: 0.0342

Gnomad4 FIN AF: 0.0877

Gnomad4 NFE AF: 0.0594

Gnomad4 OTH AF: 0.0687

Alfa AF: 0.0648 Hom.: 328

Bravo AF: 0.0761

Asia WGS AF: 0.0350 AC: 121 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jul 07, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27884173, 18252212) -

Oct 09, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:2

May 30, 2018

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 140/2178= 6.42% -

Holoprosencephaly 3 Benign:1

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	15
DANN	Benign	0.87

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

Other links and lift over

dbSNP: rs9333594; hg19: chr7-155604941; COSMIC: COSV51918674; COSMIC: COSV51918674;