7-155802875-G-C

Position:

• chr7-155802875-G-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_000193.4(SHH):​c.*25C>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 0.011 (0 hom., cov: 0)
  • Exomes 𝑓: 0.26 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: SHH NM_000193.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0110

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 7-155802875-G-C is Benign according to our data. Variant chr7-155802875-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 1198977.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SHH	NM_000193.4	c.*25C>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.*25C>G		3_prime_UTR_variant	3/3	1	NM_000193.4	ENSP00000297261.2
SHH	ENST00000430104.5	c.302-2630C>G		intron_variant		1		ENSP00000396621.1
SHH	ENST00000435425.1	n.302-2278C>G		intron_variant		1		ENSP00000413871.1
SHH	ENST00000441114.5	n.302-2208C>G		intron_variant		1		ENSP00000410546.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 545 AN: 51904 Hom.: 0 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.0109

Gnomad AMI AF: 0.00843

Gnomad AMR AF: 0.00798

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.00664

Gnomad SAS AF: 0.0128

Gnomad FIN AF: 0.0112

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0111

Gnomad OTH AF: 0.0127

GnomAD3 exomes AF: 0.0173 AC: 225 AN: 12990 Hom.: 0 AF XY: 0.0179 AC XY: 139 AN XY: 7750

Gnomad AFR exome AF: 0.00376

Gnomad AMR exome AF: 0.0639

Gnomad ASJ exome AF: 0.0110

Gnomad EAS exome AF: 0.0123

Gnomad SAS exome AF: 0.0214

Gnomad FIN exome AF: 0.0267

Gnomad NFE exome AF: 0.00832

Gnomad OTH exome AF: 0.0410

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.260 AC: 36722 AN: 141334 Hom.: 2 Cov.: 4 AF XY: 0.252 AC XY: 17905 AN XY: 71066

Gnomad4 AFR exome AF: 0.255

Gnomad4 AMR exome AF: 0.144

Gnomad4 ASJ exome AF: 0.148

Gnomad4 EAS exome AF: 0.155

Gnomad4 SAS exome AF: 0.222

Gnomad4 FIN exome AF: 0.111

Gnomad4 NFE exome AF: 0.282

Gnomad4 OTH exome AF: 0.243

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0105 AC: 547 AN: 51946 Hom.: 0 Cov.: 0 AF XY: 0.0102 AC XY: 271 AN XY: 26446

Gnomad4 AFR AF: 0.0109

Gnomad4 AMR AF: 0.00813

Gnomad4 ASJ AF: 0.0104

Gnomad4 EAS AF: 0.00665

Gnomad4 SAS AF: 0.0128

Gnomad4 FIN AF: 0.0112

Gnomad4 NFE AF: 0.0110

Gnomad4 OTH AF: 0.0126

Alfa AF: 0.00146 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 08, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.6
DANN	Benign	0.67

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: rs772915697; hg19: chr7-155595569;