rs879255648

Positions:

• chr3-128060598-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_013336.4(SEC61A1):​c.553A>G​(p.Thr185Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SEC61A1 NM_013336.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.28

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-128060598-A-G is Pathogenic according to our data. Variant chr3-128060598-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 253146.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SEC61A1	NM_013336.4	c.553A>G	p.Thr185Ala	missense_variant	7/12	ENST00000243253.8	NP_037468.1
SEC61A1	NM_001400328.1	c.571A>G	p.Thr191Ala	missense_variant	7/12		NP_001387257.1
SEC61A1	NM_001400329.1	c.394A>G	p.Thr132Ala	missense_variant	6/11		NP_001387258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SEC61A1	ENST00000243253.8	c.553A>G	p.Thr185Ala	missense_variant	7/12	1	NM_013336.4	ENSP00000243253.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hyperuricemic nephropathy, familial juvenile type 4 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 12, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	33
DANN	Uncertain	0.98
DEOGEN2	Benign	0.092	T;D;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.11
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.69	D;D;D
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.1	.;L;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-4.6	D;D;D
REVEL	Pathogenic	0.69
Sift	Benign	0.12	T;T;T
Sift4G	Benign	0.42	T;T;T
Polyphen		0.021	.;B;.
Vest4		0.75
MutPred		0.60		.;Gain of glycosylation at S180 (P = 0.4269);.;
MVP		0.92
MPC		1.2
ClinPred		0.92	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.76		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.76		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs879255648; hg19: chr3-127779441; COSMIC: COSV54579523; COSMIC: COSV54579523;