rs121917846

Variant names:

• chr5-134621002-C-T
• rs121917846
• NM_016103.4:c.109G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_016103.4(SAR1B):​c.109G>A​(p.Gly37Arg) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SAR1B NM_016103.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.86
• Publications: 7 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]

SAR1B Gene-Disease associations (from GenCC):

• chylomicron retention disease

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity SAR1B_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 3 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.81398 (below the threshold of 3.09). Trascript score misZ: 1.3781 (below the threshold of 3.09). GenCC associations: The gene is linked to chylomicron retention disease.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 5-134621002-C-T is Pathogenic according to our data. Variant chr5-134621002-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2922.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SAR1B	NM_016103.4	c.109G>A	p.Gly37Arg	missense_variant	Exon 3 of 7	ENST00000402673.7	NP_057187.1
SAR1B	NM_001033503.3	c.109G>A	p.Gly37Arg	missense_variant	Exon 4 of 8		NP_001028675.1
SAR1B	XM_047417257.1	c.109G>A	p.Gly37Arg	missense_variant	Exon 3 of 7		XP_047273213.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SAR1B	ENST00000402673.7	c.109G>A	p.Gly37Arg	missense_variant	Exon 3 of 7	1	NM_016103.4	ENSP00000385432.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00210 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Chylomicron retention disease Pathogenic:1

May 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;D;.;D
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.0	.;D;D;D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	5.2	H;H;.;.
PhyloP100		7.9
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-7.4	D;D;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Vest4		0.99
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.94
gMVP		0.89
Mutation Taster		=1/99	disease causing (ClinVar)

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: rs121917846; hg19: chr5-133956692;