5-134607045-G-C

Variant names:

• chr5-134607045-G-C
• NM_016103.4:c.502C>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_016103.4(SAR1B):​c.502C>G​(p.Leu168Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,934 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.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SAR1B NM_016103.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.91

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a chain GTP-binding protein SAR1b (size 197) in uniprot entity SAR1B_HUMAN there are 11 pathogenic changes around while only 1 benign (92%) in NM_016103.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32963556).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SAR1B	NM_016103.4	c.502C>G	p.Leu168Val	missense_variant	Exon 7 of 7	ENST00000402673.7	NP_057187.1
SAR1B	NM_001033503.3	c.502C>G	p.Leu168Val	missense_variant	Exon 8 of 8		NP_001028675.1
SAR1B	XM_047417257.1	c.502C>G	p.Leu168Val	missense_variant	Exon 7 of 7		XP_047273213.1
SAR1B	XM_047417258.1	c.298C>G	p.Leu100Val	missense_variant	Exon 5 of 5		XP_047273214.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SAR1B	ENST00000402673.7	c.502C>G	p.Leu168Val	missense_variant	Exon 7 of 7	1	NM_016103.4	ENSP00000385432.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460934 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726828

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T;.;.;T;.;T;.
Eigen	Benign	-0.12
Eigen_PC	Benign	0.016
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	.;.;.;D;D;D;T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.33	T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.6	M;.;.;M;.;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.2	N;N;N;N;N;N;N
REVEL	Uncertain	0.43
Sift	Benign	0.23	T;T;T;T;T;T;T
Sift4G	Benign	0.21	T;T;T;T;T;.;T
Polyphen		0.0020	B;.;.;B;.;.;.
Vest4		0.50
MutPred		0.46		Loss of catalytic residue at L168 (P = 0.0755);.;.;Loss of catalytic residue at L168 (P = 0.0755);.;.;Loss of catalytic residue at L168 (P = 0.0755);
MVP		0.82
MPC		0.24
ClinPred		0.19	T
GERP RS		4.0
Varity_R		0.23
gMVP		0.30

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-133942735;