3-123225264-G-T

Variant names:

• chr3-123225264-G-T
• rs1937200585
• NM_012430.5:c.508G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012430.5(SEC22A):​c.508G>T​(p.Val170Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SEC22A NM_012430.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.699

Genes affected

SEC22A (HGNC:20260): (SEC22 homolog A, vesicle trafficking protein) The protein encoded by this gene belongs to the member of the SEC22 family of vesicle trafficking proteins. This protein has similarity to rat SEC22 and may act in the early stages of the secretory pathway. [provided by RefSeq, Nov 2008]

PDIA5 (HGNC:24811): (protein disulfide isomerase family A member 5) This gene encodes a member of the disulfide isomerase (PDI) family of endoplasmic reticulum (ER) proteins that catalyze protein folding and thiol-disulfide interchange reactions. The encoded protein has an N-terminal ER-signal sequence, three catalytically active thioredoxin (TRX) domains, a TRX-like domain, and a C-terminal ER-retention sequence. The N-terminal TRX-like domain is the primary binding site for the major ER chaperone calreticulin and possibly other proteins and substrates as well. Alternative splicing results in multiple protein- and non-protein-coding transcript variants. [provided by RefSeq, Dec 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13309112).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEC22A	NM_012430.5	c.508G>T	p.Val170Phe	missense_variant	Exon 4 of 7	ENST00000492595.6	NP_036562.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEC22A	ENST00000492595.6	c.508G>T	p.Val170Phe	missense_variant	Exon 4 of 7	1	NM_012430.5	ENSP00000417972.1
SEC22A	ENST00000487572.5	c.508G>T	p.Val170Phe	missense_variant	Exon 5 of 6	3		ENSP00000420015.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.508G>T (p.V170F) alteration is located in exon 4 (coding exon 3) of the SEC22A gene. This alteration results from a G to T substitution at nucleotide position 508, causing the valine (V) at amino acid position 170 to be replaced by a phenylalanine (F). 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	0.083
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.049	T;T;T;T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.82	.;T;T;T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;.;.;L
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.2	N;N;N;N
REVEL	Benign	0.033
Sift	Benign	0.12	T;T;T;T
Sift4G	Benign	0.11	T;T;T;T
Polyphen		0.054	B;.;.;B
Vest4		0.37
MutPred		0.31		Gain of catalytic residue at V170 (P = 0.0535);Gain of catalytic residue at V170 (P = 0.0535);Gain of catalytic residue at V170 (P = 0.0535);Gain of catalytic residue at V170 (P = 0.0535);
MVP		0.20
MPC		0.16
ClinPred		0.40	T
GERP RS		2.9
Varity_R		0.069
gMVP		0.57

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: rs1937200585; hg19: chr3-122944111;