7-155802889-G-GC

Position:

• chr7-155802889-G-GC

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_000193.4(SHH):​c.*10dupG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000306 in 618,026 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: SHH NM_000193.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.133

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 Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000217 (30/137994) while in subpopulation AMR AF= 0.000568 (8/14088). AF 95% confidence interval is 0.000282. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SHH	NM_000193.4	c.*10dupG		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.*10dupG		3_prime_UTR_variant	3/3	1	NM_000193.4	ENSP00000297261.2
SHH	ENST00000430104.5	c.302-2645dupG		intron_variant		1		ENSP00000396621.1
SHH	ENST00000435425.1	n.302-2293dupG		intron_variant		1		ENSP00000413871.1
SHH	ENST00000441114.5	n.302-2223dupG		intron_variant		1		ENSP00000410546.1

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 30 AN: 137994 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000262

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000568

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000244

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000237

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000269

Gnomad OTH AF: 0.000518

GnomAD4 exome AF: 0.000331 AC: 159 AN: 480032 Hom.: 0 Cov.: 25 AF XY: 0.000279 AC XY: 65 AN XY: 232846

Gnomad4 AFR exome AF: 0.000100

Gnomad4 AMR exome AF: 0.000234

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00474

Gnomad4 SAS exome AF: 0.0000469

Gnomad4 FIN exome AF: 0.000136

Gnomad4 NFE exome AF: 0.000309

Gnomad4 OTH exome AF: 0.000292

GnomAD4 genome AF: 0.000217 AC: 30 AN: 137994 Hom.: 0 Cov.: 31 AF XY: 0.000194 AC XY: 13 AN XY: 67028

Gnomad4 AFR AF: 0.0000262

Gnomad4 AMR AF: 0.000568

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000244

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000237

Gnomad4 NFE AF: 0.000269

Gnomad4 OTH AF: 0.000518

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 02, 2021

In silico analysis suggests this variant does not impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Has not been previously published as pathogenic or benign to our knowledge; Located in the 3' untranslated region of SHH -

Computational scores

Source: dbNSFP v4.3

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: rs747055674; hg19: chr7-155595583;