chr3-128056742-T-A

Variant names:

• chr3-128056742-T-A
• rs1553721236
• NM_013336.4:c.254T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_013336.4(SEC61A1):​c.254T>A​(p.Val85Asp) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SEC61A1 NM_013336.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.02
• Publications: 1 publications found

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]

SEC61A1 Gene-Disease associations (from GenCC):

• hyperuricemic nephropathy, familial juvenile type 4

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• SEC61A1 deficiency

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.938
• PP5: Variant 3-128056742-T-A is Pathogenic according to our data. Variant chr3-128056742-T-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 549498.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEC61A1	NM_013336.4	c.254T>A	p.Val85Asp	missense_variant	Exon 5 of 12	ENST00000243253.8	NP_037468.1
SEC61A1	NM_001400328.1	c.272T>A	p.Val91Asp	missense_variant	Exon 5 of 12		NP_001387257.1
SEC61A1	NM_001400329.1	c.95T>A	p.Val32Asp	missense_variant	Exon 4 of 11		NP_001387258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEC61A1	ENST00000243253.8	c.254T>A	p.Val85Asp	missense_variant	Exon 5 of 12	1	NM_013336.4	ENSP00000243253.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Immunodeficiency, common variable, 15 Pathogenic:1

Jan 12, 2024

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Decreased circulating immunoglobulin concentration Pathogenic:1

Apr 16, 2018

SIB Swiss Institute of Bioinformatics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as a Likely Pathogenic, for Hypogammaglobulinemia, Autosomal Dominant inheritance. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PP1-Moderate => PP1 upgraded in strength to Moderate (PMID:28782633). PS3-Moderate => PS3 downgraded in strength to Moderate (PMID:28782633). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	31
DANN	Uncertain	0.98
DEOGEN2	Benign	0.35	T;D;T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Pathogenic	3.4	.;M;.
PhyloP100		8.0
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-6.3	D;D;D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.97
MutPred		0.78		.;Gain of phosphorylation at T86 (P = 0.1343);.;
MVP		0.89
MPC		3.0
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		1.0
Mutation Taster		=1/99	disease causing (ClinVar)

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: rs1553721236; hg19: chr3-127775585;