7-16462951-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_015464.3(SOSTDC1):ā€‹c.218T>Cā€‹(p.Val73Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000193 in 1,563,264 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.

Frequency

Genomes: š‘“ 0.000099 ( 0 hom., cov: 32)
Exomes š‘“: 0.00020 ( 0 hom. )

Consequence

SOSTDC1
NM_015464.3 missense

Scores

5
9
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.97
Variant links:
Genes affected
SOSTDC1 (HGNC:21748): (sclerostin domain containing 1) This gene is a member of the sclerostin family and encodes an N-glycosylated, secreted protein with a C-terminal cystine knot-like domain. This protein functions as a bone morphogenetic protein (BMP) antagonist. Specifically, it directly associates with BMPs, prohibiting them from binding their receptors, thereby regulating BMP signaling during cellular proliferation, differentiation, and programmed cell death. [provided by RefSeq, Jul 2008]
CRPPA (HGNC:37276): (CDP-L-ribitol pyrophosphorylase A) This gene encodes a 2-C-methyl-D-erythritol 4-phosphate cytidylyltransferase-like protein. Mutations in this gene are the cause of Walker-Warburg syndrome. Alternate splicing results in multiple transcript variants. [provided by RefSeq, May 2012]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.29230845).
BS2
High AC in GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SOSTDC1NM_015464.3 linkc.218T>C p.Val73Ala missense_variant 2/2 ENST00000307068.5 NP_056279.1 Q6X4U4-1A4D125
LOC105375168XR_007060220.1 linkn.736+1635A>G intron_variant
LOC105375168XR_007060223.1 linkn.581-7669A>G intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SOSTDC1ENST00000307068.5 linkc.218T>C p.Val73Ala missense_variant 2/21 NM_015464.3 ENSP00000304930.4 Q6X4U4-1
SOSTDC1ENST00000396652.1 linkc.290T>C p.Val97Ala missense_variant 5/52 ENSP00000379889.1 Q6X4U4-2
CRPPAENST00000675257.1 linkc.-47+33429T>C intron_variant ENSP00000501664.1 A0A6Q8PF75
CRPPAENST00000674759.1 linkc.-47+33429T>C intron_variant ENSP00000502749.1 A0A6Q8PHI3

Frequencies

GnomAD3 genomes
AF:
0.0000986
AC:
15
AN:
152188
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000206
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000854
AC:
19
AN:
222390
Hom.:
0
AF XY:
0.0000831
AC XY:
10
AN XY:
120274
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:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000174
Gnomad OTH exome
AF:
0.000191
GnomAD4 exome
AF:
0.000203
AC:
286
AN:
1411076
Hom.:
0
Cov.:
31
AF XY:
0.000213
AC XY:
148
AN XY:
694826
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000259
Gnomad4 OTH exome
AF:
0.000103
GnomAD4 genome
AF:
0.0000986
AC:
15
AN:
152188
Hom.:
0
Cov.:
32
AF XY:
0.000148
AC XY:
11
AN XY:
74364
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000206
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000639
Hom.:
0
Bravo
AF:
0.0000756
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.0000906
AC:
11

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 26, 2024The c.218T>C (p.V73A) alteration is located in exon 2 (coding exon 2) of the SOSTDC1 gene. This alteration results from a T to C substitution at nucleotide position 218, causing the valine (V) at amino acid position 73 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.71
BayesDel_addAF
Benign
0.0055
T
BayesDel_noAF
Uncertain
0.040
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.68
D;.
Eigen
Pathogenic
0.76
Eigen_PC
Pathogenic
0.75
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.89
D;D
M_CAP
Benign
0.082
D
MetaRNN
Benign
0.29
T;T
MetaSVM
Uncertain
0.24
D
MutationAssessor
Uncertain
2.3
M;.
PrimateAI
Uncertain
0.56
T
PROVEAN
Benign
-2.4
N;N
REVEL
Pathogenic
0.65
Sift
Uncertain
0.018
D;D
Sift4G
Uncertain
0.057
T;T
Polyphen
0.98
D;.
Vest4
0.48
MVP
0.80
MPC
1.0
ClinPred
0.38
T
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.31
gMVP
0.55

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: rs201667417; hg19: chr7-16502576; COSMIC: COSV61049879; API