rs1480063398

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_ModerateBP6_ModerateBS2

The NM_000193.4(SHH):​c.964G>A​(p.Asp322Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000142 in 1,474,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

SHH
NM_000193.4 missense

Scores

2
4
13

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.924
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 -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.26150632).
BP6
Variant 7-155803325-C-T is Benign according to our data. Variant chr7-155803325-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 464840.Status of the report is criteria_provided_single_submitter, 1 stars.
BS2
High AC in GnomAdExome4 at 20 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SHHNM_000193.4 linkuse as main transcriptc.964G>A p.Asp322Asn missense_variant 3/3 ENST00000297261.7 NP_000184.1 Q15465

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SHHENST00000297261.7 linkuse as main transcriptc.964G>A p.Asp322Asn missense_variant 3/31 NM_000193.4 ENSP00000297261.2 Q15465
SHHENST00000430104.5 linkuse as main transcriptc.301+2971G>A intron_variant 1 ENSP00000396621.1 C9JC48
SHHENST00000435425.1 linkuse as main transcriptn.302-2728G>A intron_variant 1 ENSP00000413871.1 F8WEH4
SHHENST00000441114.5 linkuse as main transcriptn.302-2658G>A intron_variant 1 ENSP00000410546.1 F8WB84

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
151892
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000130
AC:
1
AN:
76644
Hom.:
0
AF XY:
0.0000226
AC XY:
1
AN XY:
44248
show subpopulations
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 SAS exome
AF:
0.0000635
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000151
AC:
20
AN:
1322186
Hom.:
0
Cov.:
35
AF XY:
0.0000291
AC XY:
19
AN XY:
652060
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000263
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.50e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
151892
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74214
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Holoprosencephaly 3 Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 10, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.082
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Benign
-0.36
CADD
Benign
15
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.64
D
Eigen
Benign
-0.56
Eigen_PC
Benign
-0.46
FATHMM_MKL
Benign
0.47
N
LIST_S2
Benign
0.52
T
M_CAP
Pathogenic
0.94
D
MetaRNN
Benign
0.26
T
MetaSVM
Uncertain
0.66
D
MutationAssessor
Benign
1.5
L
PrimateAI
Pathogenic
0.93
D
PROVEAN
Benign
-0.19
N
REVEL
Uncertain
0.36
Sift
Benign
0.54
T
Sift4G
Benign
0.56
T
Polyphen
0.0090
B
Vest4
0.024
MutPred
0.44
Gain of MoRF binding (P = 0.0314);
MVP
0.62
ClinPred
0.071
T
GERP RS
3.7
Varity_R
0.070
gMVP
0.43

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: rs1480063398; hg19: chr7-155596019; API