7-155806606-C-T

Position:

• chr7-155806606-C-T

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.301-49G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.575 in 1,609,018 control chromosomes in the GnomAD database, including 273,620 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (21090 hom., cov: 32)
  • Exomes 𝑓: 0.58 (252530 hom.)
• Consequence: SHH NM_000193.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.782

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=-0.82).
• BP6: Variant 7-155806606-C-T is Benign according to our data. Variant chr7-155806606-C-T is described in ClinVar as [Benign]. Clinvar id is 255495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.64 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SHH	NM_000193.4	c.301-49G>A		intron_variant		ENST00000297261.7	NP_000184.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SHH	ENST00000297261.7	c.301-49G>A		intron_variant		1	NM_000193.4	ENSP00000297261	P1

Frequencies

GnomAD3 genomes AF: 0.492 AC: 74782 AN: 151938 Hom.: 21076 Cov.: 32

Gnomad AFR AF: 0.204

Gnomad AMI AF: 0.709

Gnomad AMR AF: 0.617

Gnomad ASJ AF: 0.522

Gnomad EAS AF: 0.608

Gnomad SAS AF: 0.659

Gnomad FIN AF: 0.687

Gnomad MID AF: 0.509

Gnomad NFE AF: 0.584

Gnomad OTH AF: 0.508

GnomAD3 exomes AF: 0.591 AC: 144464 AN: 244498 Hom.: 44512 AF XY: 0.597 AC XY: 79515 AN XY: 133198

Gnomad AFR exome AF: 0.193

Gnomad AMR exome AF: 0.699

Gnomad ASJ exome AF: 0.533

Gnomad EAS exome AF: 0.604

Gnomad SAS exome AF: 0.660

Gnomad FIN exome AF: 0.686

Gnomad NFE exome AF: 0.581

Gnomad OTH exome AF: 0.579

GnomAD4 exome AF: 0.583 AC: 849993 AN: 1456962 Hom.: 252530 Cov.: 35 AF XY: 0.585 AC XY: 423938 AN XY: 724860

Gnomad4 AFR exome AF: 0.189

Gnomad4 AMR exome AF: 0.689

Gnomad4 ASJ exome AF: 0.525

Gnomad4 EAS exome AF: 0.611

Gnomad4 SAS exome AF: 0.654

Gnomad4 FIN exome AF: 0.688

Gnomad4 NFE exome AF: 0.583

Gnomad4 OTH exome AF: 0.564

GnomAD4 genome AF: 0.492 AC: 74815 AN: 152056 Hom.: 21090 Cov.: 32 AF XY: 0.503 AC XY: 37373 AN XY: 74324

Gnomad4 AFR AF: 0.204

Gnomad4 AMR AF: 0.618

Gnomad4 ASJ AF: 0.522

Gnomad4 EAS AF: 0.607

Gnomad4 SAS AF: 0.659

Gnomad4 FIN AF: 0.687

Gnomad4 NFE AF: 0.584

Gnomad4 OTH AF: 0.510

Alfa AF: 0.526 Hom.: 6247

Bravo AF: 0.472

Asia WGS AF: 0.605 AC: 2105 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Microphthalmia, isolated, with coloboma 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Solitary median maxillary central incisor syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Holoprosencephaly 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.7
DANN	Benign	0.69

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: rs1233555; hg19: chr7-155599300; COSMIC: COSV51918728;