4-82842139-C-A

Variant names:

• chr4-82842139-C-A
• rs78735860
• NM_001077207.4:c.2968+1G>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PVS1_Moderate BP6 BS2

The NM_001077207.4(SEC31A):​c.2968+1G>T variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.000514 in 1,551,340 control chromosomes in the GnomAD database, including 3 homozygotes. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00032 (2 hom.)
• Consequence: SEC31A NM_001077207.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 7.11
• Publications: 3 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: Likely_benign. The variant received -3 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.093366094 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.4, offset of -27, new splice context is: ccaGTgagc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• BP6: Variant 4-82842139-C-A is Benign according to our data. Variant chr4-82842139-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3044225.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 Unknown,AR gene

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.2968+1G>T		splice_donor intron	N/A	NP_001070675.1	O94979-1
	SEC31A	NM_001400154.1		c.3061+1G>T		splice_donor intron	N/A	NP_001387083.1	D6REX3
	SEC31A	NM_001400155.1		c.3061+1G>T		splice_donor intron	N/A	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.2968+1G>T		splice_donor intron	N/A	ENSP00000378721.2	O94979-1
	SEC31A	ENST00000508502.5	TSL:1	c.2923+46G>T		intron	N/A	ENSP00000424635.1	O94979-2
	SEC31A	ENST00000348405.8	TSL:1	c.2851+1G>T		splice_donor intron	N/A	ENSP00000337602.5	O94979-4

Frequencies

GnomAD3 genomes AF: 0.00229 AC: 348 AN: 152194 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00777

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000860 AC: 175 AN: 203450 AF XY: 0.000632

Gnomad AFR exome AF: 0.00794

Gnomad AMR exome AF: 0.00108

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000127

Gnomad OTH exome AF: 0.00167

GnomAD4 exome AF: 0.000320 AC: 447 AN: 1399028 Hom.: 2 Cov.: 31 AF XY: 0.000290 AC XY: 200 AN XY: 688550

African (AFR) AF: 0.00776 AC: 247 AN: 31848

American (AMR) AF: 0.00113 AC: 42 AN: 37090

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21488

East Asian (EAS) AF: 0.00 AC: 0 AN: 39214

South Asian (SAS) AF: 0.0000133 AC: 1 AN: 75296

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50862

Middle Eastern (MID) AF: 0.00206 AC: 11 AN: 5332

European-Non Finnish (NFE) AF: 0.0000861 AC: 93 AN: 1080246

Other (OTH) AF: 0.000919 AC: 53 AN: 57652

GnomAD4 genome AF: 0.00230 AC: 351 AN: 152312 Hom.: 1 Cov.: 31 AF XY: 0.00209 AC XY: 156 AN XY: 74478

African (AFR) AF: 0.00782 AC: 325 AN: 41562

American (AMR) AF: 0.000915 AC: 14 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68020

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.000948 Hom.: 1

Bravo AF: 0.00268

ESP6500AA AF: 0.00635 AC: 28

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000925 AC: 112

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	SEC31A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		7.1
GERP RS		5.8
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.84		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.84		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs78735860; hg19: chr4-83763292;