4-82819090-T-G

Variant names:

• chr4-82819090-T-G
• rs142745636
• NM_001077207.4:c.3647A>C

Variant summary

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

The NM_001077207.4(SEC31A):​c.3647A>C​(p.Asn1216Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000689 in 1,451,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. N1216S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SEC31A NM_001077207.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.23
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with spastic quadriplegia, optic atrophy, seizures, and structural brain anomalies

  Inheritance: AR, Unknown Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)

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=0.2734297).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001077207.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEC31A	NM_001077207.4	MANE Select	c.3647A>C	p.Asn1216Thr	missense	Exon 27 of 27	NP_001070675.1	O94979-1
	SEC31A	NM_001400154.1		c.3740A>C	p.Asn1247Thr	missense	Exon 28 of 28	NP_001387083.1	D6REX3
	SEC31A	NM_001400155.1		c.3740A>C	p.Asn1247Thr	missense	Exon 28 of 28	NP_001387084.1	D6REX3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEC31A	ENST00000395310.7	TSL:1 MANE Select	c.3647A>C	p.Asn1216Thr	missense	Exon 27 of 27	ENSP00000378721.2	O94979-1
	SEC31A	ENST00000508502.5	TSL:1	c.3602A>C	p.Asn1201Thr	missense	Exon 27 of 27	ENSP00000424635.1	O94979-2
	SEC31A	ENST00000348405.8	TSL:1	c.3530A>C	p.Asn1177Thr	missense	Exon 25 of 25	ENSP00000337602.5	O94979-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451214 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 721408

African (AFR) AF: 0.00 AC: 0 AN: 33052

American (AMR) AF: 0.00 AC: 0 AN: 42330

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25756

East Asian (EAS) AF: 0.00 AC: 0 AN: 39556

South Asian (SAS) AF: 0.00 AC: 0 AN: 83066

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108310

Other (OTH) AF: 0.00 AC: 0 AN: 60056

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.059	T
Eigen	Benign	0.10
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.5	L
PhyloP100		4.2
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.041
Sift	Benign	0.36	T
Sift4G	Benign	0.43	T
Polyphen		0.015	B
Vest4		0.49
MutPred		0.22		Loss of stability (P = 0.0915)
MVP		0.48
MPC		0.23
ClinPred		0.56	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.090
gMVP		0.15
Mutation Taster		=67/33	polymorphism

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: rs142745636; hg19: chr4-83740243;