rs104894047

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000193.4(SHH):​c.869G>A​(p.Gly290Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,529,318 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0023 ( 7 hom., cov: 33)
Exomes 𝑓: 0.0011 ( 18 hom. )

Consequence

SHH
NM_000193.4 missense

Scores

2
3
13

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1U:1B:7

Conservation

PhyloP100: 0.804
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.06371763).
BP6
Variant 7-155803420-C-T is Benign according to our data. Variant chr7-155803420-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 8887.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-155803420-C-T is described in Lovd as [Likely_benign]. Variant chr7-155803420-C-T is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00233 (354/152130) while in subpopulation EAS AF= 0.0343 (176/5134). AF 95% confidence interval is 0.0301. There are 7 homozygotes in gnomad4. There are 209 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 354 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SHHNM_000193.4 linkc.869G>A p.Gly290Asp missense_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.869G>A p.Gly290Asp missense_variant Exon 3 of 3 1 NM_000193.4 ENSP00000297261.2 Q15465
SHHENST00000430104.5 linkc.301+2876G>A intron_variant Intron 3 of 3 1 ENSP00000396621.1 C9JC48
SHHENST00000435425.1 linkn.302-2823G>A intron_variant Intron 3 of 4 1 ENSP00000413871.1 F8WEH4
SHHENST00000441114.5 linkn.302-2753G>A intron_variant Intron 3 of 4 1 ENSP00000410546.1 F8WB84

Frequencies

GnomAD3 genomes
AF:
0.00233
AC:
354
AN:
152020
Hom.:
7
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000748
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00374
Gnomad EAS
AF:
0.0342
Gnomad SAS
AF:
0.00393
Gnomad FIN
AF:
0.00897
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000265
Gnomad OTH
AF:
0.000479
GnomAD3 exomes
AF:
0.00331
AC:
414
AN:
125120
Hom.:
6
AF XY:
0.00309
AC XY:
213
AN XY:
68864
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000415
Gnomad ASJ exome
AF:
0.00357
Gnomad EAS exome
AF:
0.0308
Gnomad SAS exome
AF:
0.00111
Gnomad FIN exome
AF:
0.00672
Gnomad NFE exome
AF:
0.000172
Gnomad OTH exome
AF:
0.00181
GnomAD4 exome
AF:
0.00112
AC:
1536
AN:
1377188
Hom.:
18
Cov.:
35
AF XY:
0.00108
AC XY:
737
AN XY:
679334
show subpopulations
Gnomad4 AFR exome
AF:
0.000132
Gnomad4 AMR exome
AF:
0.000113
Gnomad4 ASJ exome
AF:
0.00353
Gnomad4 EAS exome
AF:
0.0232
Gnomad4 SAS exome
AF:
0.00138
Gnomad4 FIN exome
AF:
0.00747
Gnomad4 NFE exome
AF:
0.000111
Gnomad4 OTH exome
AF:
0.00235
GnomAD4 genome
AF:
0.00233
AC:
354
AN:
152130
Hom.:
7
Cov.:
33
AF XY:
0.00281
AC XY:
209
AN XY:
74392
show subpopulations
Gnomad4 AFR
AF:
0.000746
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00374
Gnomad4 EAS
AF:
0.0343
Gnomad4 SAS
AF:
0.00393
Gnomad4 FIN
AF:
0.00897
Gnomad4 NFE
AF:
0.000265
Gnomad4 OTH
AF:
0.000474
Alfa
AF:
0.00118
Hom.:
0
Bravo
AF:
0.00174
ExAC
AF:
0.00114
AC:
99

ClinVar

Significance: Benign/Likely benign
Submissions summary: Pathogenic:1Uncertain:1Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Holoprosencephaly 3 Pathogenic:1Uncertain:1Benign:1
May 01, 2010
OMIM
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Jan 12, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 29, 2013
GeneReviews
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: curation

- -

not provided Benign:3
Mar 05, 2018
Athena Diagnostics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 23, 2019
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 32939873, 31180159, 20425842, 18655123, 10556296, 19533790) -

Sep 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

SHH: PP2, PP3, BS1, BS2 -

not specified Benign:1
Oct 20, 2014
Eurofins Ntd Llc (ga)
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

SHH-related disorder Benign:1
Apr 25, 2019
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Schizencephaly;C1840235:Solitary median maxillary central incisor syndrome;C1840529:Holoprosencephaly 3;C1968843:Microphthalmia, isolated, with coloboma 5 Benign:1
Dec 28, 2021
Fulgent Genetics, Fulgent Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.081
BayesDel_addAF
Benign
-0.12
T
BayesDel_noAF
Uncertain
0.080
CADD
Benign
8.7
DANN
Benign
0.77
DEOGEN2
Uncertain
0.67
D
Eigen
Benign
-0.73
Eigen_PC
Benign
-0.89
FATHMM_MKL
Benign
0.23
N
LIST_S2
Benign
0.53
T
MetaRNN
Benign
0.064
T
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Benign
1.9
L
PrimateAI
Pathogenic
0.85
D
PROVEAN
Benign
-0.47
N
REVEL
Uncertain
0.59
Sift
Benign
0.21
T
Sift4G
Benign
0.27
T
Polyphen
0.55
P
Vest4
0.68
MVP
1.0
ClinPred
0.017
T
GERP RS
0.85
Varity_R
0.063
gMVP
0.70

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs104894047; hg19: chr7-155596114; API