7-155802865-G-C

Position:

• chr7-155802865-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_000193.4(SHH):​c.*35C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (0 hom., cov: 24)
  • Exomes 𝑓: 0.31 (263 hom.)
  • Failed GnomAD Quality Control
• Consequence: SHH NM_000193.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.460

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 7-155802865-G-C is Benign according to our data. Variant chr7-155802865-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 1213157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SHH	NM_000193.4	c.*35C>G		3_prime_UTR_variant	3/3	ENST00000297261.7	NP_000184.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SHH	ENST00000297261	c.*35C>G		3_prime_UTR_variant	3/3	1	NM_000193.4	ENSP00000297261.2
SHH	ENST00000430104.5	c.302-2620C>G		intron_variant		1		ENSP00000396621.1
SHH	ENST00000435425.1	n.302-2268C>G		intron_variant		1		ENSP00000413871.1
SHH	ENST00000441114.5	n.302-2198C>G		intron_variant		1		ENSP00000410546.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1208 AN: 78318 Hom.: 0 Cov.: 24 FAILED QC

Gnomad AFR AF: 0.0142

Gnomad AMI AF: 0.0140

Gnomad AMR AF: 0.0121

Gnomad ASJ AF: 0.0128

Gnomad EAS AF: 0.0216

Gnomad SAS AF: 0.0269

Gnomad FIN AF: 0.0158

Gnomad MID AF: 0.00417

Gnomad NFE AF: 0.0159

Gnomad OTH AF: 0.0125

GnomAD3 exomes AF: 0.0379 AC: 299 AN: 7882 Hom.: 1 AF XY: 0.0385 AC XY: 174 AN XY: 4518

Gnomad AFR exome AF: 0.0301

Gnomad AMR exome AF: 0.177

Gnomad ASJ exome AF: 0.0229

Gnomad EAS exome AF: 0.0612

Gnomad SAS exome AF: 0.0637

Gnomad FIN exome AF: 0.0311

Gnomad NFE exome AF: 0.0196

Gnomad OTH exome AF: 0.0366

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.306 AC: 32526 AN: 106166 Hom.: 263 Cov.: 4 AF XY: 0.301 AC XY: 16494 AN XY: 54860

Gnomad4 AFR exome AF: 0.305

Gnomad4 AMR exome AF: 0.265

Gnomad4 ASJ exome AF: 0.233

Gnomad4 EAS exome AF: 0.256

Gnomad4 SAS exome AF: 0.291

Gnomad4 FIN exome AF: 0.195

Gnomad4 NFE exome AF: 0.329

Gnomad4 OTH exome AF: 0.296

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0154 AC: 1208 AN: 78386 Hom.: 0 Cov.: 24 AF XY: 0.0150 AC XY: 586 AN XY: 39102

Gnomad4 AFR AF: 0.0143

Gnomad4 AMR AF: 0.0121

Gnomad4 ASJ AF: 0.0128

Gnomad4 EAS AF: 0.0217

Gnomad4 SAS AF: 0.0264

Gnomad4 FIN AF: 0.0158

Gnomad4 NFE AF: 0.0159

Gnomad4 OTH AF: 0.0124

Alfa AF: 0.000542 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 15, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.2
DANN	Benign	0.61

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: rs768929857; hg19: chr7-155595559;