5-134607069-A-G

Position:

chr5-134607069-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_016103.4(SAR1B):c.481-3T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000267 in 1,540,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

SAR1B
NM_016103.4 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.0001792

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.623

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000282 (43/152244) while in subpopulation AFR AF= 0.000748 (31/41464). AF 95% confidence interval is 0.00054. There are 0 homozygotes in gnomad4. There are 20 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
SAR1B	NM_016103.4 linkuse as main transcript	c.481-3T>C	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	ENST00000402673.7	NP_057187.1
SAR1B	NM_001033503.3 linkuse as main transcript	c.481-3T>C	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		NP_001028675.1
SAR1B	XM_047417257.1 linkuse as main transcript	c.481-3T>C	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		XP_047273213.1
SAR1B	XM_047417258.1 linkuse as main transcript	c.277-3T>C	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		XP_047273214.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SAR1B	ENST00000402673.7 linkuse as main transcript	c.481-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_016103.4	ENSP00000385432	P1

Frequencies

GnomAD3 genomes

AF:

0.000282

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000748

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000917

AC:

AN:

250954

Hom.:

AF XY:

0.0000516

AC XY:

AN XY:

135612

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000794

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000266

AC:

369

AN:

1388476

Hom.:

Cov.:

AF XY:

0.000259

AC XY:

180

AN XY:

695242

show subpopulations

Gnomad4 AFR exome

AF:

0.000594

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000390

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000354

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000318

Gnomad4 OTH exome

AF:

0.000190

GnomAD4 genome

AF:

0.000282

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.000748

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000422

Hom.:

Bravo

AF:

0.000321

EpiCase

AF:

0.000273

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 2021

The c.481-3T>C intronic alteration consists of a T to C substitution 3 nucleotides before exon 8 (coding exon 6) of the SAR1B gene. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 24, 2022

This sequence change falls in intron 7 of the SAR1B gene. It does not directly change the encoded amino acid sequence of the SAR1B protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs369515030, gnomAD 0.08%). 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: 1055550). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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

BayesDel_noAF

Benign

-0.79

CADD

Benign

6.0

DANN

Benign

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00018

dbscSNV1_RF

Benign

0.040

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