NM_003144.5:c.829G>A

Variant names:

• chr6-7289896-C-T
• rs774238351
• NM_003144.5:c.829G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003144.5(SSR1):​c.829G>A​(p.Ala277Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000072 in 1,389,552 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A277P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: SSR1 NM_003144.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.02
• Publications: 0 publications found

Genes affected

SSR1 (HGNC:11323): (signal sequence receptor subunit 1) The signal sequence receptor (SSR) is a glycosylated endoplasmic reticulum (ER) membrane receptor associated with protein translocation across the ER membrane. The SSR consists of 2 subunits, a 34-kD glycoprotein encoded by this gene and a 22-kD glycoprotein. This gene generates several mRNA species as a result of complex alternative polyadenylation. This gene is unusual in that it utilizes arrays of polyA signal sequences that are mostly non-canonical. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2014]

ENSG00000238221 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17560154).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003144.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SSR1	NM_003144.5	MANE Select	c.829G>A	p.Ala277Thr	missense	Exon 8 of 8	NP_003135.2	P43307-1
	SSR1	NM_001292008.2		c.625G>A	p.Ala209Thr	missense	Exon 8 of 8	NP_001278937.1	C9JBX5
	SSR1	NR_120448.2		n.829G>A		non_coding_transcript_exon	Exon 7 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SSR1	ENST00000244763.9	TSL:1 MANE Select	c.829G>A	p.Ala277Thr	missense	Exon 8 of 8	ENSP00000244763.4	P43307-1
	SSR1	ENST00000916206.1		c.976G>A	p.Ala326Thr	missense	Exon 9 of 9	ENSP00000586265.1
	SSR1	ENST00000474597.5	TSL:5	c.844G>A	p.Ala282Thr	missense	Exon 9 of 10	ENSP00000418617.1	C9IZQ1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.20e-7 AC: 1 AN: 1389552 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 689774

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 28342

American (AMR) AF: 0.00 AC: 0 AN: 27326

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24064

East Asian (EAS) AF: 0.00 AC: 0 AN: 34556

South Asian (SAS) AF: 0.00 AC: 0 AN: 72128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52868

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5618

European-Non Finnish (NFE) AF: 9.20e-7 AC: 1 AN: 1087112

Other (OTH) AF: 0.00 AC: 0 AN: 57538

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.053	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.027
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.14	N
PhyloP100		3.0
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	0.27	N
REVEL	Benign	0.048
Sift	Benign	0.41	T
Sift4G	Benign	0.56	T
Polyphen		0.0080	B
Vest4		0.20
MutPred		0.38		Gain of phosphorylation at A277 (P = 0.0031)
MVP		0.51
MPC		0.29
ClinPred		0.58	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.32
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

dbSNP: rs774238351; hg19: chr6-7290129;