14-39040770-T-C

Position:

chr14-39040770-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The ENST00000307712.11(SEC23A):c.2104A>G(p.Met702Val) variant causes a missense change. The variant allele was found at a frequency of 0.000471 in 1,614,212 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.00033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00049 ( 0 hom. )

Consequence

SEC23A
ENST00000307712.11 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 6.13

Variant links:

Genes affected

SEC23A (HGNC:10701): (SEC23 homolog A, COPII coat complex component) The protein encoded by this gene is a member of the SEC23 subfamily of the SEC23/SEC24 family. It is part of a protein complex and found in the ribosome-free transitional face of the endoplasmic reticulum (ER) and associated vesicles. This protein has similarity to yeast Sec23p component of COPII. COPII is the coat protein complex responsible for vesicle budding from the ER. The encoded protein is suggested to play a role in the ER-Golgi protein trafficking. [provided by RefSeq, Jul 2008]

SEC23A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.18283859).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SEC23A	NM_006364.4 linkuse as main transcript	c.2104A>G	p.Met702Val	missense_variant	18/20	ENST00000307712.11	NP_006355.2
SEC23A	XM_005267262.2 linkuse as main transcript	c.2176A>G	p.Met726Val	missense_variant	19/21		XP_005267319.1
SEC23A	XM_011536355.4 linkuse as main transcript	c.2176A>G	p.Met726Val	missense_variant	19/21		XP_011534657.1
SEC23A	XM_017020928.3 linkuse as main transcript	c.2104A>G	p.Met702Val	missense_variant	18/20		XP_016876417.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SEC23A	ENST00000307712.11 linkuse as main transcript	c.2104A>G	p.Met702Val	missense_variant	18/20	1	NM_006364.4	ENSP00000306881	P1	Q15436-1

Frequencies

GnomAD3 genomes

AF:

0.000328

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000603

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000318

AC:

AN:

251456

Hom.:

AF XY:

0.000324

AC XY:

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000528

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.000486

AC:

710

AN:

1461874

Hom.:

Cov.:

AF XY:

0.000484

AC XY:

352

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000425

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.000112

Gnomad4 NFE exome

AF:

0.000580

Gnomad4 OTH exome

AF:

0.000447

GnomAD4 genome

AF:

0.000328

AC:

AN:

152338

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000603

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000550

Hom.:

Bravo

AF:

0.000400

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000280

AC:

EpiCase

AF:

0.000818

EpiControl

AF:

0.000948

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Craniolenticulosutural dysplasia

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 26, 2023	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects SEC23A function (PMID: 22298774). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SEC23A protein function. ClinVar contains an entry for this variant (Variation ID: 39521). This missense change has been observed in individual(s) with Craniolenticulosutural dysplasia (PMID: 21039434). This variant is present in population databases (rs138568622, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 702 of the SEC23A protein (p.Met702Val). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2011	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Uncertain

0.0

CADD

Benign

DANN

Benign

0.45

DEOGEN2

Benign

0.11

.;T;.

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.088

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Benign

0.0098

MetaRNN

Benign

0.18

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.68

.;N;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-1.4

N;N;N

REVEL

Benign

0.22

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.037, 0.0020

.;B;B

Vest4

0.79

MVP

0.75

MPC

0.40

ClinPred

0.023

GERP RS

4.6

Varity_R

0.32

gMVP

0.52

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over