3-156548935-C-T

Variant names:

• chr3-156548935-C-T
• rs554757087
• NM_007107.5:c.329G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_007107.5(SSR3):​c.329G>A​(p.Arg110Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000112 in 1,613,508 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: SSR3 NM_007107.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.01

Genes affected

SSR3 (HGNC:11325): (signal sequence receptor subunit 3) The signal sequence receptor (SSR) is a glycosylated endoplasmic reticulum (ER) membrane receptor associated with protein translocation across the ER membrane. The SSR is comprised of four membrane proteins/subunits: alpha, beta, gamma, and delta. The first two are glycosylated subunits and the latter two are non-glycosylated subunits. This gene encodes the gamma subunit, which is predicted to span the membrane four times. [provided by RefSeq, Aug 2010]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.009923577).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SSR3	NM_007107.5	c.329G>A	p.Arg110Lys	missense_variant	Exon 3 of 5	ENST00000265044.7	NP_009038.1
SSR3	NM_001308197.2	c.329G>A	p.Arg110Lys	missense_variant	Exon 3 of 5		NP_001295126.1
SSR3	NM_001308204.2	c.173G>A	p.Arg58Lys	missense_variant	Exon 3 of 5		NP_001295133.1
SSR3	NM_001308205.2	c.173G>A	p.Arg58Lys	missense_variant	Exon 3 of 5		NP_001295134.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SSR3	ENST00000265044.7	c.329G>A	p.Arg110Lys	missense_variant	Exon 3 of 5	1	NM_007107.5	ENSP00000265044.2

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152140 Hom.: 0 Cov.: 33

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: 0.00125

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000223 AC: 56 AN: 251032 Hom.: 0 AF XY: 0.000287 AC XY: 39 AN XY: 135714

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000116 AC: 170 AN: 1461250 Hom.: 1 Cov.: 35 AF XY: 0.000158 AC XY: 115 AN XY: 726942

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152258 Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8 AN XY: 74440

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000677 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.000247 AC: 30

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Dec 07, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 110 of the SSR3 protein (p.Arg110Lys). This variant is present in population databases (rs554757087, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with SSR3-related conditions. ClinVar contains an entry for this variant (Variation ID: 2171056). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	18
DANN	Benign	0.84
DEOGEN2	Benign	0.14	T;.;T;T;T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D;D;D;.;D
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.0099	T;T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	-3.0	N;N;.;.;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	1.4	N;N;N;N;N
REVEL	Benign	0.13
Sift	Benign	1.0	T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.0010	B;.;.;.;.
Vest4		0.20
MutPred		0.38		Gain of glycosylation at S105 (P = 0.0037);Gain of glycosylation at S105 (P = 0.0037);Gain of glycosylation at S105 (P = 0.0037);.;.;
MVP		0.34
MPC		0.30
ClinPred		0.067	T
GERP RS		5.4
Varity_R		0.25
gMVP		0.54

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: rs554757087; hg19: chr3-156266724;