5-134649138-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35971186).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEC24A	NM_021982.3	c.62G>C	p.Gly21Ala	missense_variant	Exon 1 of 23	ENST00000398844.7	NP_068817.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SAR1B	ENST00000507419.5	c.-1240C>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 7	1		ENSP00000425339.1
SEC24A	ENST00000398844.7	c.62G>C	p.Gly21Ala	missense_variant	Exon 1 of 23	2	NM_021982.3	ENSP00000381823.2
SEC24A	ENST00000322887.8	c.62G>C	p.Gly21Ala	missense_variant	Exon 1 of 13	1		ENSP00000321749.4
SAR1B	ENST00000507419.5	c.-1240C>G		5_prime_UTR_variant	Exon 1 of 7	1		ENSP00000425339.1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 12, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.62G>C (p.G21A) alteration is located in exon 1 (coding exon 1) of the SEC24A gene. This alteration results from a G to C substitution at nucleotide position 62, causing the glycine (G) at amino acid position 21 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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;T
M_CAP	Pathogenic	0.46	D
MetaRNN	Benign	0.36	T;T
MetaSVM	Uncertain	0.79	D
MutationAssessor	Uncertain	2.1	M;M
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.53	N;N
REVEL	Uncertain	0.39
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.34	T;T
Polyphen		1.0	D;.
Vest4		0.30
MutPred		0.31		Loss of loop (P = 9e-04);Loss of loop (P = 9e-04);
MVP		0.93
MPC		0.11
ClinPred		0.59	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.27
gMVP		0.64

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

Other links and lift over

dbSNP: rs1372082335; hg19: chr5-133984828;