chr5-134608443-C-G

Variant names:

• chr5-134608443-C-G
• rs28942109
• NM_016103.4:c.409G>C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Strong

The NM_016103.4(SAR1B):​c.409G>C​(p.Asp137His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D137N) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SAR1B NM_016103.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.91
• Publications: 1 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 11 ACMG points.

• PM1: In a chain GTP-binding protein SAR1b (size 197) in uniprot entity SAR1B_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_016103.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-134608443-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 2923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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, 0.993

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SAR1B	NM_016103.4	c.409G>C	p.Asp137His	missense_variant	Exon 6 of 7	ENST00000402673.7	NP_057187.1
SAR1B	NM_001033503.3	c.409G>C	p.Asp137His	missense_variant	Exon 7 of 8		NP_001028675.1
SAR1B	XM_047417257.1	c.409G>C	p.Asp137His	missense_variant	Exon 6 of 7		XP_047273213.1
SAR1B	XM_047417258.1	c.205G>C	p.Asp69His	missense_variant	Exon 4 of 5		XP_047273214.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SAR1B	ENST00000402673.7	c.409G>C	p.Asp137His	missense_variant	Exon 6 of 7	1	NM_016103.4	ENSP00000385432.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459646 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 725948

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44552

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25964

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 85934

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52926

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111060

Other (OTH) AF: 0.00 AC: 0 AN: 60328

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;.;.;D;.;D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;.;.;D;D;D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	5.2	H;.;.;H;.;.;.
PhyloP100		7.9
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-6.5	D;D;D;D;D;D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;.;D
Polyphen		1.0	D;.;.;D;.;.;.
Vest4		0.99
MutPred		0.98		Gain of disorder (P = 0.1776);.;.;Gain of disorder (P = 0.1776);.;.;Gain of disorder (P = 0.1776);
MVP		1.0
MPC		0.88
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.98
gMVP		0.83
Mutation Taster		=2/98	disease causing

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

Other links and lift over

dbSNP: rs28942109; hg19: chr5-133944133;