7-155802954-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate

The NM_000193.4(SHH):​c.1335G>A​(p.Trp445*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000716 in 1,397,370 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

SHH
NM_000193.4 stop_gained

Scores

2
4
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 2.87

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_pathogenic. The variant received 6 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0389 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 7-155802954-C-T is Pathogenic according to our data. Variant chr7-155802954-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1676094.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SHHNM_000193.4 linkc.1335G>A p.Trp445* stop_gained 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.1335G>A p.Trp445* stop_gained Exon 3 of 3 1 NM_000193.4 ENSP00000297261.2 Q15465
SHHENST00000430104.5 linkc.302-2709G>A intron_variant Intron 3 of 3 1 ENSP00000396621.1 C9JC48
SHHENST00000435425.1 linkn.302-2357G>A intron_variant Intron 3 of 4 1 ENSP00000413871.1 F8WEH4
SHHENST00000441114.5 linkn.302-2287G>A intron_variant Intron 3 of 4 1 ENSP00000410546.1 F8WB84

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
7.16e-7
AC:
1
AN:
1397370
Hom.:
0
Cov.:
35
AF XY:
0.00000144
AC XY:
1
AN XY:
693948
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
30132
American (AMR)
AF:
0.00
AC:
0
AN:
38362
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
24800
East Asian (EAS)
AF:
0.00
AC:
0
AN:
34292
South Asian (SAS)
AF:
0.00
AC:
0
AN:
77844
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
50740
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4506
European-Non Finnish (NFE)
AF:
9.27e-7
AC:
1
AN:
1079308
Other (OTH)
AF:
0.00
AC:
0
AN:
57386
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Jan 01, 2022
CeGaT Center for Human Genetics Tuebingen
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.52
D
BayesDel_noAF
Pathogenic
0.51
CADD
Pathogenic
38
DANN
Uncertain
0.99
Eigen
Uncertain
0.63
Eigen_PC
Uncertain
0.43
FATHMM_MKL
Uncertain
0.91
D
PhyloP100
2.9
Vest4
0.86
GERP RS
3.0
Mutation Taster
=15/185
disease causing

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: rs2117124779; hg19: chr7-155595648; API