chr7-155802875-G-C

Variant names:

• chr7-155802875-G-C
• rs772915697
• NM_000193.4:c.*25C>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.*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
• 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=-0.86).
• 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 rank	MANE	Protein	UniProt
SHH	NM_000193.4	c.*25C>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.*25C>G		3_prime_UTR_variant	Exon 3 of 3	1	NM_000193.4	ENSP00000297261.2
SHH	ENST00000430104.5	c.302-2630C>G		intron_variant	Intron 3 of 3	1		ENSP00000396621.1
SHH	ENST00000435425.1	n.302-2278C>G		intron_variant	Intron 3 of 4	1		ENSP00000413871.1
SHH	ENST00000441114.5	n.302-2208C>G		intron_variant	Intron 3 of 4	1		ENSP00000410546.1

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 545 AN: 51904 Hom.: 0 Cov.: 0

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

GnomAD2 exomes AF: 0.0173 AC: 225 AN: 12990 AF XY: 0.0179

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 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

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

African (AFR) AF: 0.255 AC: 706 AN: 2768

American (AMR) AF: 0.144 AC: 249 AN: 1734

Ashkenazi Jewish (ASJ) AF: 0.148 AC: 469 AN: 3174

East Asian (EAS) AF: 0.155 AC: 606 AN: 3908

South Asian (SAS) AF: 0.222 AC: 1489 AN: 6720

European-Finnish (FIN) AF: 0.111 AC: 794 AN: 7158

Middle Eastern (MID) AF: 0.211 AC: 88 AN: 418

European-Non Finnish (NFE) AF: 0.282 AC: 30842 AN: 109358

Other (OTH) AF: 0.243 AC: 1479 AN: 6096

⚠️ 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: 0.0105 AC: 547 AN: 51946 Hom.: 0 Cov.: 0 AF XY: 0.0102 AC XY: 271 AN XY: 26446

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

African (AFR) AF: 0.0109 AC: 148 AN: 13542

American (AMR) AF: 0.00813 AC: 47 AN: 5784

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 13 AN: 1256

East Asian (EAS) AF: 0.00665 AC: 14 AN: 2104

South Asian (SAS) AF: 0.0128 AC: 20 AN: 1566

European-Finnish (FIN) AF: 0.0112 AC: 37 AN: 3318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 134

European-Non Finnish (NFE) AF: 0.0110 AC: 256 AN: 23170

Other (OTH) AF: 0.0126 AC: 9 AN: 716

⚠️ 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: 0.00146 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 08, 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	-0.86
CADD	Benign	4.6
DANN	Benign	0.67
PhyloP100		-0.011
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: rs772915697; hg19: chr7-155595569;