5-134607045-G-T

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>A(p.Leu168Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,934 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 (★). Synonymous variant affecting the same amino acid position (i.e. L168L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SAR1B NM_016103.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 15 pathogenic changes around while only 1 benign (94%) in NM_016103.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3093726).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SAR1B	NM_016103.4	c.502C>A	p.Leu168Met	missense_variant	7/7	ENST00000402673.7
SAR1B	NM_001033503.3	c.502C>A	p.Leu168Met	missense_variant	8/8
SAR1B	XM_047417257.1	c.502C>A	p.Leu168Met	missense_variant	7/7
SAR1B	XM_047417258.1	c.298C>A	p.Leu100Met	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SAR1B	ENST00000402673.7	c.502C>A	p.Leu168Met	missense_variant	7/7	1	NM_016103.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251246 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135764

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460934 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 168 of the SAR1B protein (p.Leu168Met). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with SAR1B-related conditions. ClinVar contains an entry for this variant (Variation ID: 1492286). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.16	T;.;.;T;.;T;.
Eigen	Benign	-0.11
Eigen_PC	Benign	0.030
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.31	T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Uncertain	2.2	M;.;.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.0	N;N;N;N;N;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.14	T;T;T;T;T;T;T
Sift4G	Benign	0.13	T;T;T;T;T;.;T
Polyphen		0.16	B;.;.;B;.;.;.
Vest4		0.44
MutPred		0.46		Loss of catalytic residue at L168 (P = 0.0474);.;.;Loss of catalytic residue at L168 (P = 0.0474);.;.;Loss of catalytic residue at L168 (P = 0.0474);
MVP		0.81
MPC		0.36
ClinPred		0.18	T
GERP RS		4.0
Varity_R		0.33
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1175873618; hg19: chr5-133942735;