rs28942109

Positions:

chr5-134608443-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_016103.4(SAR1B):c.409G>A(p.Asp137Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,610,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

SAR1B
NM_016103.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5O:1

Conservation

PhyloP100: 7.91

Variant links:

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 links:

SAR1B (HGNC:):

SAR1B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 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, 0.99

PP5

Variant 5-134608443-C-T is Pathogenic according to our data. Variant chr5-134608443-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-134608443-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SAR1B	NM_016103.4 linkuse as main transcript	c.409G>A	p.Asp137Asn	missense_variant	6/7	ENST00000402673.7	NP_057187.1	Q9Y6B6
SAR1B	NM_001033503.3 linkuse as main transcript	c.409G>A	p.Asp137Asn	missense_variant	7/8		NP_001028675.1	Q9Y6B6
SAR1B	XM_047417257.1 linkuse as main transcript	c.409G>A	p.Asp137Asn	missense_variant	6/7		XP_047273213.1
SAR1B	XM_047417258.1 linkuse as main transcript	c.205G>A	p.Asp69Asn	missense_variant	4/5		XP_047273214.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SAR1B	ENST00000402673.7 linkuse as main transcript	c.409G>A	p.Asp137Asn	missense_variant	6/7	1	NM_016103.4	ENSP00000385432.2		Q9Y6B6

Frequencies

GnomAD3 genomes

AF:

0.0000331

AC:

AN:

151006

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000660

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000589

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000242

AC:

AN:

248362

Hom.:

AF XY:

0.0000372

AC XY:

AN XY:

134238

show subpopulations

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:

0.0000534

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000301

AC:

AN:

1459646

Hom.:

Cov.:

AF XY:

0.0000427

AC XY:

AN XY:

725948

show subpopulations

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:

0.0000360

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000331

AC:

AN:

151006

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73606

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000660

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000589

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000469

Hom.:

Bravo

AF:

0.0000378

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Chylomicron retention disease

Pathogenic:3Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 19, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2008	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 28, 2017	The p.Asp137Asn (NM_001033503.2 c.409G>A) variant in SAR1B has been reported in at least 5 homozygous and 3 compound heterozygous individuals of French Canadian or White Canadian ancestry with Chylomicron retention disease and segregated in 5 family members (Charcosset 2008, Peretti 2009, and Jones 2003). This variant has also been reported in ClinVar (Variation ID#2923). This variant has been ide ntified in 0.004% (2/53,150) of European chromosomes by the Exome Aggregation Co nsortium (ExAC, http://exac.broadinstitute.org; dbSNP rs28942109). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tool s and conservation analysis suggest that the p.Asp137Asn variant may impact the protein, though this information is not predictive enough to determine pathogeni city. In summary, although additional studies are required to fully establish it s clinical significance, the p.Asp137Asn variant is likely pathogenic based upon biallelic case observations and segregation in affected individuals. -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 07, 2023	For these reasons, this variant has been classified as Pathogenic. 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 2923). This missense change has been observed in individuals with Anderson's disease and/or chylomicron retention disease (PMID: 12692552, 17945526). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs28942109, gnomAD 0.005%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 137 of the SAR1B protein (p.Asp137Asn). -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 22, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.73

D;.;.;D;.;D;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

.;.;.;D;D;D;D

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.7

H;.;.;H;.;.;.

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-4.6

D;D;D;D;D;D;D

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0010

D;D;D;D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D;.;D

Polyphen

1.0

D;.;.;D;.;.;.

Vest4

0.98

MutPred

0.99

Gain of catalytic residue at D137 (P = 0.1315);.;.;Gain of catalytic residue at D137 (P = 0.1315);.;.;Gain of catalytic residue at D137 (P = 0.1315);

MVP

1.0

MPC

0.48

ClinPred

1.0

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.94

gMVP

0.74

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over