7-155802865-G-C

Variant names:

• chr7-155802865-G-C
• rs768929857
• NM_000193.4:c.*35C>G

Variant summary

Our verdict is Benign. The variant received -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
• 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: Benign. The variant received -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 rank	MANE	Protein	UniProt
SHH	NM_000193.4	c.*35C>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.*35C>G		3_prime_UTR_variant	Exon 3 of 3	1	NM_000193.4	ENSP00000297261.2
SHH	ENST00000430104.5	c.302-2620C>G		intron_variant	Intron 3 of 3	1		ENSP00000396621.1
SHH	ENST00000435425.1	n.302-2268C>G		intron_variant	Intron 3 of 4	1		ENSP00000413871.1
SHH	ENST00000441114.5	n.302-2198C>G		intron_variant	Intron 3 of 4	1		ENSP00000410546.1

Frequencies

GnomAD3 genomes AF: 0.0154 AC: 1208 AN: 78318 Hom.: 0 Cov.: 24

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

GnomAD2 exomes AF: 0.0379 AC: 299 AN: 7882 AF XY: 0.0385

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 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

African (AFR) AF: 0.305 AC: 736 AN: 2414

American (AMR) AF: 0.265 AC: 592 AN: 2238

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 738 AN: 3162

East Asian (EAS) AF: 0.256 AC: 1316 AN: 5144

South Asian (SAS) AF: 0.291 AC: 1499 AN: 5154

European-Finnish (FIN) AF: 0.195 AC: 1590 AN: 8136

Middle Eastern (MID) AF: 0.281 AC: 105 AN: 374

European-Non Finnish (NFE) AF: 0.329 AC: 24281 AN: 73898

Other (OTH) AF: 0.296 AC: 1669 AN: 5646

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

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

African (AFR) AF: 0.0143 AC: 293 AN: 20526

American (AMR) AF: 0.0121 AC: 102 AN: 8408

Ashkenazi Jewish (ASJ) AF: 0.0128 AC: 24 AN: 1880

East Asian (EAS) AF: 0.0217 AC: 64 AN: 2954

South Asian (SAS) AF: 0.0264 AC: 62 AN: 2350

European-Finnish (FIN) AF: 0.0158 AC: 77 AN: 4870

Middle Eastern (MID) AF: 0.00455 AC: 1 AN: 220

European-Non Finnish (NFE) AF: 0.0159 AC: 565 AN: 35618

Other (OTH) AF: 0.0124 AC: 14 AN: 1130

⚠️ 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: 0.000542 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 15, 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	-0.90
CADD	Benign	3.2
DANN	Benign	0.61
PhyloP100		-0.46
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: rs768929857; hg19: chr7-155595559;