7-16462765-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_015464.3(SOSTDC1):c.404A>G(p.Asn135Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,614,196 control chromosomes in the GnomAD database, including 165 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.010 (12 hom., cov: 32)
  • Exomes 𝑓: 0.013 (153 hom.)
• Consequence: SOSTDC1 NM_015464.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.32

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]

LOC105375168 (HGNC:):

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008537382).
• BP6: Variant 7-16462765-T-C is Benign according to our data. Variant chr7-16462765-T-C is described in ClinVar as [Benign]. Clinvar id is 2657327.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 1564 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOSTDC1	NM_015464.3	c.404A>G	p.Asn135Ser	missense_variant	2/2	ENST00000307068.5
LOC105375168	XR_007060223.1	n.581-7855T>C		intron_variant, non_coding_transcript_variant
LOC105375168	XR_007060220.1	n.736+1449T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOSTDC1	ENST00000307068.5	c.404A>G	p.Asn135Ser	missense_variant	2/2	1	NM_015464.3	P1
SOSTDC1	ENST00000396652.1	c.476A>G	p.Asn159Ser	missense_variant	5/5	2
CRPPA	ENST00000674759.1	c.-47+33615A>G		intron_variant
CRPPA	ENST00000675257.1	c.-47+33615A>G		intron_variant

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1564 AN: 152190 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00263

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.00968

Gnomad ASJ AF: 0.0303

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00621

Gnomad FIN AF: 0.00631

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0152

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.0104 AC: 2620 AN: 251318 Hom.: 29 AF XY: 0.0112 AC XY: 1516 AN XY: 135816

Gnomad AFR exome AF: 0.00277

Gnomad AMR exome AF: 0.00726

Gnomad ASJ exome AF: 0.0255

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00552

Gnomad FIN exome AF: 0.00661

Gnomad NFE exome AF: 0.0148

Gnomad OTH exome AF: 0.0126

GnomAD4 exome AF: 0.0128 AC: 18643 AN: 1461888 Hom.: 153 Cov.: 31 AF XY: 0.0127 AC XY: 9241 AN XY: 727244

Gnomad4 AFR exome AF: 0.00245

Gnomad4 AMR exome AF: 0.00789

Gnomad4 ASJ exome AF: 0.0271

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00569

Gnomad4 FIN exome AF: 0.00605

Gnomad4 NFE exome AF: 0.0142

Gnomad4 OTH exome AF: 0.0135

GnomAD4 genome AF: 0.0103 AC: 1563 AN: 152308 Hom.: 12 Cov.: 32 AF XY: 0.0101 AC XY: 753 AN XY: 74482

Gnomad4 AFR AF: 0.00262

Gnomad4 AMR AF: 0.00961

Gnomad4 ASJ AF: 0.0303

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00621

Gnomad4 FIN AF: 0.00631

Gnomad4 NFE AF: 0.0152

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.0142 Hom.: 29

Bravo AF: 0.0106

TwinsUK AF: 0.0221 AC: 82

ALSPAC AF: 0.0119 AC: 46

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.0164 AC: 141

ExAC AF: 0.0100 AC: 1214

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0167

EpiControl AF: 0.0186

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

CRPPA: BS1, BS2; SOSTDC1: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.59	D;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.95	D;D
MetaRNN	Benign	0.0085	T;T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	2.0	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.4	N;N
REVEL	Uncertain	0.34
Sift	Benign	0.68	T;T
Sift4G	Benign	0.70	T;T
Polyphen		0.85	P;.
Vest4		0.42
MPC		0.39
ClinPred		0.029	T
GERP RS		5.7
Varity_R		0.20
gMVP		0.58

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

Other links and lift over

dbSNP: rs143801072; hg19: chr7-16502390; COSMIC: COSV99063788;