3-156544339-A-G

Position:

• chr3-156544339-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_007107.5(SSR3):​c.460T>C​(p.Phe154Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SSR3 NM_007107.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.20

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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SSR3	NM_007107.5	c.460T>C	p.Phe154Leu	missense_variant	4/5	ENST00000265044.7	NP_009038.1
SSR3	NM_001308197.2	c.499T>C	p.Phe167Leu	missense_variant	4/5		NP_001295126.1
SSR3	NM_001308204.2	c.304T>C	p.Phe102Leu	missense_variant	4/5		NP_001295133.1
SSR3	NM_001308205.2	c.304T>C	p.Phe102Leu	missense_variant	4/5		NP_001295134.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SSR3	ENST00000265044.7	c.460T>C	p.Phe154Leu	missense_variant	4/5	1	NM_007107.5	ENSP00000265044.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2021

The c.460T>C (p.F154L) alteration is located in exon 4 (coding exon 4) of the SSR3 gene. This alteration results from a T to C substitution at nucleotide position 460, causing the phenylalanine (F) at amino acid position 154 to be replaced by a leucine (L). 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	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.71	D;.;T;T;T
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;.;D
M_CAP	Benign	0.032	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Pathogenic	2.9	M;.;.;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-4.6	D;D;D;D;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0050	D;D;D;D;D
Sift4G	Uncertain	0.050	T;D;T;D;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.87
MutPred		0.93		.;Loss of sheet (P = 0.0817);.;.;.;
MVP		0.51
MPC		1.1
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.55
gMVP		0.79

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-156262128;