14-39040770-T-A

Variant names:

• chr14-39040770-T-A
• rs138568622
• NM_006364.4:c.2104A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006364.4(SEC23A):​c.2104A>T​(p.Met702Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M702V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SEC23A NM_006364.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.13
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• craniolenticulosutural dysplasia

  Inheritance: AR, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4129097).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEC23A	NM_006364.4	c.2104A>T	p.Met702Leu	missense_variant	Exon 18 of 20	ENST00000307712.11	NP_006355.2
SEC23A	XM_005267262.2	c.2176A>T	p.Met726Leu	missense_variant	Exon 19 of 21		XP_005267319.1
SEC23A	XM_011536355.4	c.2176A>T	p.Met726Leu	missense_variant	Exon 19 of 21		XP_011534657.1
SEC23A	XM_017020928.3	c.2104A>T	p.Met702Leu	missense_variant	Exon 18 of 20		XP_016876417.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEC23A	ENST00000307712.11	c.2104A>T	p.Met702Leu	missense_variant	Exon 18 of 20	1	NM_006364.4	ENSP00000306881.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	22
DANN	Benign	0.71
DEOGEN2	Benign	0.095	.;T;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.044
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.41	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.47	.;N;.
PhyloP100		6.1
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.0	N;N;N
REVEL	Benign	0.16
Sift	Benign	0.77	T;T;T
Sift4G	Benign	0.91	T;T;T
Polyphen		0.0040, 0.0010	.;B;B
Vest4		0.70
MutPred		0.64		.;Gain of catalytic residue at R699 (P = 6e-04);.;
MVP		0.74
MPC		0.36
ClinPred		0.61	D
GERP RS		4.6
Varity_R		0.33
gMVP		0.40
Mutation Taster		=17/83	disease causing

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: rs138568622; hg19: chr14-39509974;