rs752745051

Variant names:

• chr3-128055731-T-G
• rs752745051
• NM_013336.4:c.200T>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_013336.4(SEC61A1):​c.200T>G​(p.Val67Gly) 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. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SEC61A1 NM_013336.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.02

Genes affected

SEC61A1 (HGNC:18276): (SEC61 translocon subunit alpha 1) The protein encoded by this gene belongs to the SECY/SEC61- alpha family. It appears to play a crucial role in the insertion of secretory and membrane polypeptides into the endoplasmic reticulum. This protein found to be tightly associated with membrane-bound ribosomes, either directly or through adaptor proteins. This gene encodes an alpha subunit of the heteromeric SEC61 complex, which also contains beta and gamma subunits. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.79
• PP5: Variant 3-128055731-T-G is Pathogenic according to our data. Variant chr3-128055731-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 253147.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEC61A1	NM_013336.4	c.200T>G	p.Val67Gly	missense_variant	Exon 4 of 12	ENST00000243253.8	NP_037468.1
SEC61A1	NM_001400328.1	c.218T>G	p.Val73Gly	missense_variant	Exon 4 of 12		NP_001387257.1
SEC61A1	NM_001400329.1	c.41T>G	p.Val14Gly	missense_variant	Exon 3 of 11		NP_001387258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEC61A1	ENST00000243253.8	c.200T>G	p.Val67Gly	missense_variant	Exon 4 of 12	1	NM_013336.4	ENSP00000243253.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hyperuricemic nephropathy, familial juvenile type 4 Pathogenic:1

Feb 26, 2025

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T;D;T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Benign	0.027	D
MetaRNN	Pathogenic	0.79	D;D;D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Uncertain	2.1	.;M;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.4	D;D;D
REVEL	Uncertain	0.43
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		0.49	.;P;.
Vest4		0.89
MutPred		0.49		.;Loss of stability (P = 0.0034);.;
MVP		0.81
MPC		1.8
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.92
gMVP		0.96

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: rs752745051; hg19: chr3-127774574;