7-155802871-T-C

Variant names:

• chr7-155802871-T-C
• rs767315773
• NM_000193.4:c.*29A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_000193.4(SHH):​c.*29A>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 0.020 (0 hom., cov: 0)
  • Exomes 𝑓: 0.30 (5 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: -2.79
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• holoprosencephaly 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• microphthalmia, isolated, with coloboma 5

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia
• polydactyly of a triphalangeal thumb

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• solitary median maxillary central incisor syndrome

  Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: G2P, Ambry Genetics
• skeletal system disorder

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• autosomal dominant preaxial polydactyly-upperback hypertrichosis syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hypoplastic tibiae-postaxial polydactyly syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• microphthalmia, isolated, with coloboma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• syndactyly type 4

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• triphalangeal thumb-polysyndactyly syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• holoprosencephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 7-155802871-T-C is Benign according to our data. Variant chr7-155802871-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 1200869.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHH	NM_000193.4	c.*29A>G		3_prime_UTR_variant	Exon 3 of 3	ENST00000297261.7	NP_000184.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHH	ENST00000297261.7	c.*29A>G		3_prime_UTR_variant	Exon 3 of 3	1	NM_000193.4	ENSP00000297261.2
SHH	ENST00000430104.5	c.302-2626A>G		intron_variant	Intron 3 of 3	1		ENSP00000396621.1
SHH	ENST00000435425.1	n.302-2274A>G		intron_variant	Intron 3 of 4	1		ENSP00000413871.1
SHH	ENST00000441114.5	n.302-2204A>G		intron_variant	Intron 3 of 4	1		ENSP00000410546.1

Frequencies

GnomAD3 genomes AF: 0.0202 AC: 895 AN: 44274 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0203

Gnomad AMI AF: 0.0139

Gnomad AMR AF: 0.0139

Gnomad ASJ AF: 0.0175

Gnomad EAS AF: 0.0186

Gnomad SAS AF: 0.0247

Gnomad FIN AF: 0.0173

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0227

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.0290 AC: 335 AN: 11538 AF XY: 0.0296

Gnomad AFR exome AF: 0.00862

Gnomad AMR exome AF: 0.115

Gnomad ASJ exome AF: 0.0212

Gnomad EAS exome AF: 0.0492

Gnomad FIN exome AF: 0.0303

Gnomad NFE exome AF: 0.0169

Gnomad OTH exome AF: 0.0474

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.302 AC: 53314 AN: 176720 Hom.: 5 Cov.: 5 AF XY: 0.293 AC XY: 25921 AN XY: 88324

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.298 AC: 1087 AN: 3644

American (AMR) AF: 0.171 AC: 418 AN: 2442

Ashkenazi Jewish (ASJ) AF: 0.177 AC: 694 AN: 3916

East Asian (EAS) AF: 0.165 AC: 928 AN: 5620

South Asian (SAS) AF: 0.269 AC: 1861 AN: 6910

European-Finnish (FIN) AF: 0.127 AC: 1110 AN: 8774

Middle Eastern (MID) AF: 0.251 AC: 136 AN: 542

European-Non Finnish (NFE) AF: 0.328 AC: 44914 AN: 136824

Other (OTH) AF: 0.269 AC: 2166 AN: 8048

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0202 AC: 897 AN: 44324 Hom.: 0 Cov.: 0 AF XY: 0.0192 AC XY: 444 AN XY: 23182

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0204 AC: 236 AN: 11580

American (AMR) AF: 0.0141 AC: 74 AN: 5248

Ashkenazi Jewish (ASJ) AF: 0.0175 AC: 17 AN: 970

East Asian (EAS) AF: 0.0187 AC: 33 AN: 1764

South Asian (SAS) AF: 0.0240 AC: 34 AN: 1418

European-Finnish (FIN) AF: 0.0173 AC: 57 AN: 3298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 136

European-Non Finnish (NFE) AF: 0.0227 AC: 431 AN: 18992

Other (OTH) AF: 0.0171 AC: 12 AN: 702

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0590 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 23, 2019

GeneDx

Significance: Likely 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	-0.88
CADD	Benign	1.4
DANN	Benign	0.57
PhyloP100		-2.8
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs767315773; hg19: chr7-155595565;