4-82829002-T-C

Position:

• chr4-82829002-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001077207.4(SEC31A):​c.3025A>G​(p.Lys1009Glu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SEC31A NM_001077207.4 missense, splice_region
• Scores: Splicing: ADA: 0.9293
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.13

Genes affected

SEC31A (HGNC:17052): (SEC31 homolog A, COPII coat complex component) The protein encoded by this gene shares similarity with the yeast Sec31 protein, and is a component of the outer layer of the coat protein complex II (COPII). The encoded protein is involved in vesicle budding from the endoplasmic reticulum (ER) and contains multiple WD repeats near the N-terminus and a proline-rich region in the C-terminal half. It associates with the protein encoded by the SEC13 homolog, nuclear pore and COPII coat complex component (SEC13), and is required for ER-Golgi transport. Monoubiquitylation of this protein by CUL3-KLHL12 was found to regulate the size of COPII coats to accommodate unusually shaped cargo. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2015]

SEC31A (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2650051).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SEC31A	NM_001077207.4	c.3025A>G	p.Lys1009Glu	missense_variant, splice_region_variant	23/27	ENST00000395310.7	NP_001070675.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SEC31A	ENST00000395310.7	c.3025A>G	p.Lys1009Glu	missense_variant, splice_region_variant	23/27	1	NM_001077207.4	ENSP00000378721.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

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

Sep 08, 2024

The c.3025A>G (p.K1009E) alteration is located in exon 23 (coding exon 22) of the SEC31A gene. This alteration results from a A to G substitution at nucleotide position 3025, causing the lysine (K) at amino acid position 1009 to be replaced by a glutamic acid (E). 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	Benign	0.29
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.045	.;.;T;.;.;.;T;T;.;.;T;.;.
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.89	D;.;.;D;.;T;D;D;T;D;.;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.27	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.8	.;.;L;.;.;.;L;.;.;.;L;.;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.8	N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.045	D;T;D;T;T;T;D;D;T;T;D;D;T
Sift4G	Benign	0.31	T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.027	B;D;B;.;D;D;B;.;D;B;B;.;.
Vest4		0.62
MutPred		0.37		.;.;Loss of methylation at K1009 (P = 0.0101);.;.;.;Loss of methylation at K1009 (P = 0.0101);.;.;.;Loss of methylation at K1009 (P = 0.0101);.;.;
MVP		0.37
MPC		0.23
ClinPred		0.75	D
GERP RS		5.6
Varity_R		0.19
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.93
dbscSNV1_RF	Benign	0.48
SpliceAI score (max)		0.080		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: chr4-83750155;