ENST00000507419.5:c.-1240C>G

Variant names:

• chr5-134649138-G-C
• rs1372082335
• ENST00000507419.5:c.-1240C>G

Variant summary

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

The ENST00000507419.5(SAR1B):​c.-1240C>G variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.000000686 in 1,457,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SAR1B ENST00000507419.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.50
• Publications: 0 publications found

Genes affected

SAR1B (HGNC:10535): (secretion associated Ras related GTPase 1B) The protein encoded by this gene is a small GTPase that acts as a homodimer. The encoded protein is activated by the guanine nucleotide exchange factor PREB and is involved in protein transport from the endoplasmic reticulum to the Golgi. This protein is part of the COPII coat complex. Defects in this gene are a cause of chylomicron retention disease (CMRD), also known as Anderson disease (ANDD). Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Mar 2010]

SEC24A (HGNC:10703): (SEC24 homolog A, COPII coat complex component) The protein encoded by this gene belongs to a family of proteins that are homologous to yeast Sec24. This protein is a component of coat protein II (COPII)-coated vesicles that mediate protein transport from the endoplasmic reticulum. COPII acts in the cytoplasm to promote the transport of secretory, plasma membrane, and vacuolar proteins from the endoplasmic reticulum to the golgi complex. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2011]

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=0.35971186).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000507419.5. 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
	SEC24A	NM_021982.3	MANE Select	c.62G>C	p.Gly21Ala	missense	Exon 1 of 23	NP_068817.1	O95486-1
	SEC24A	NM_001252231.2		c.62G>C	p.Gly21Ala	missense	Exon 1 of 13	NP_001239160.1	O95486-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SAR1B	ENST00000507419.5	TSL:1	c.-1240C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	ENSP00000425339.1	Q9H029
	SEC24A	ENST00000398844.7	TSL:2 MANE Select	c.62G>C	p.Gly21Ala	missense	Exon 1 of 23	ENSP00000381823.2	O95486-1
	SEC24A	ENST00000322887.8	TSL:1	c.62G>C	p.Gly21Ala	missense	Exon 1 of 13	ENSP00000321749.4	O95486-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457762 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725088

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33216

American (AMR) AF: 0.00 AC: 0 AN: 44300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26044

East Asian (EAS) AF: 0.00 AC: 0 AN: 39252

South Asian (SAS) AF: 0.00 AC: 0 AN: 85484

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53126

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110374

Other (OTH) AF: 0.00 AC: 0 AN: 60214

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.032	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.46	D
MetaRNN	Benign	0.36	T
MetaSVM	Uncertain	0.79	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.5
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.53	N
REVEL	Uncertain	0.39
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.34	T
Polyphen		1.0	D
Vest4		0.30
MutPred		0.31		Loss of loop (P = 9e-04)
MVP		0.93
MPC		0.11
ClinPred		0.59	D
GERP RS		5.1
PromoterAI		0.024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.27
gMVP		0.64
Mutation Taster		=83/17	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: rs1372082335; hg19: chr5-133984828;