chr5-134606975-C-A

Variant names:

• chr5-134606975-C-A
• rs200409139
• NM_016103.4:c.572G>T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_016103.4(SAR1B):​c.572G>T​(p.Arg191Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SAR1B NM_016103.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.91

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 5 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SAR1B	NM_016103.4	c.572G>T	p.Arg191Leu	missense_variant	Exon 7 of 7	ENST00000402673.7	NP_057187.1
SAR1B	NM_001033503.3	c.572G>T	p.Arg191Leu	missense_variant	Exon 8 of 8		NP_001028675.1
SAR1B	XM_047417257.1	c.572G>T	p.Arg191Leu	missense_variant	Exon 7 of 7		XP_047273213.1
SAR1B	XM_047417258.1	c.368G>T	p.Arg123Leu	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.572G>T	p.Arg191Leu	missense_variant	Exon 7 of 7	1	NM_016103.4	ENSP00000385432.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T;.;.;T;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;.;.;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Pathogenic	2.9	M;.;.;M;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.2	D;D;D;D;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.033	D;D;D;D;D
Polyphen		0.98	D;.;.;D;.
Vest4		0.80
MutPred		0.56		Loss of MoRF binding (P = 6e-04);.;.;Loss of MoRF binding (P = 6e-04);.;
MVP		0.88
MPC		0.82
ClinPred		0.99	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.82
gMVP		0.65

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: rs200409139; hg19: chr5-133942665;