chr7-155806720-G-C

Variant names:

• chr7-155806720-G-C
• rs4716913
• ENST00000430104.5:c.30C>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The ENST00000430104.5(SHH):​c.30C>G​(p.Pro10Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 692,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P10P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SHH ENST00000430104.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.625
• Publications: 3 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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP7: Synonymous conserved (PhyloP=0.625 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHH	NM_000193.4	c.301-163C>G		intron_variant	Intron 1 of 2	ENST00000297261.7	NP_000184.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHH	ENST00000297261.7	c.301-163C>G		intron_variant	Intron 1 of 2	1	NM_000193.4	ENSP00000297261.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000665 AC: 1 AN: 150388 AF XY: 0.0000123

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000175

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000145 AC: 1 AN: 692018 Hom.: 0 Cov.: 9 AF XY: 0.00000274 AC XY: 1 AN XY: 365458

African (AFR) AF: 0.00 AC: 0 AN: 18102

American (AMR) AF: 0.00 AC: 0 AN: 34718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20284

East Asian (EAS) AF: 0.00 AC: 0 AN: 32978

South Asian (SAS) AF: 0.00 AC: 0 AN: 64614

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47824

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3828

European-Non Finnish (NFE) AF: 0.00000230 AC: 1 AN: 434950

Other (OTH) AF: 0.00 AC: 0 AN: 34720

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.9
DANN	Benign	0.46
PhyloP100		0.63

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: rs4716913; hg19: chr7-155599414;