7-155800129-A-G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000193.4(SHH):​c.*2771T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000626 in 319,308 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000063 ( 0 hom. )

Consequence

SHH
NM_000193.4 3_prime_UTR

Scores

2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.315

Publications

0 publications found
Variant links:
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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.69).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SHHNM_000193.4 linkc.*2771T>C 3_prime_UTR_variant Exon 3 of 3 ENST00000297261.7 NP_000184.1 Q15465

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SHHENST00000297261.7 linkc.*2771T>C 3_prime_UTR_variant Exon 3 of 3 1 NM_000193.4 ENSP00000297261.2 Q15465

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000626
AC:
2
AN:
319308
Hom.:
0
Cov.:
0
AF XY:
0.00000555
AC XY:
1
AN XY:
180334
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
8634
American (AMR)
AF:
0.0000733
AC:
2
AN:
27290
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
10790
East Asian (EAS)
AF:
0.00
AC:
0
AN:
9216
South Asian (SAS)
AF:
0.00
AC:
0
AN:
59744
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
27208
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
2790
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
159156
Other (OTH)
AF:
0.00
AC:
0
AN:
14480
⚠️ 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.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.400
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jun 26, 2025
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant summary: SHH c.*2771T>C is located in the untranslated mRNA region downstream of the termination codon. The variant was absent in 151222 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.*2771T>C in individuals affected with SHH-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.69
CADD
Benign
5.6
DANN
Benign
0.61
PhyloP100
0.32

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

Other links and lift over

dbSNP: rs1803147658; hg19: chr7-155592823; API