Genetic Variant SARAF:p.Val67Ile (chr8-30073960-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_016127.6(SARAF):c.199G>A(p.Val67Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,614,212 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

SARAF
NM_016127.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.41

Variant links:

Genes affected

SARAF (HGNC:28789): (store-operated calcium entry associated regulatory factor) Involved in regulation of store-operated calcium entry. Located in endoplasmic reticulum and endoplasmic reticulum-plasma membrane contact site. Is integral component of endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

SARAF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1174849).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SARAF	NM_016127.6 link	c.199G>A	p.Val67Ile	missense_variant	Exon 2 of 6	ENST00000256255.11	NP_057211.4	Q96BY9-1A0A140VK59
SARAF	NM_001284239.1 link	c.-234-3901G>A		intron_variant	Intron 1 of 4		NP_001271168.1	Q96BY9-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SARAF	ENST00000256255.11 link	c.199G>A	p.Val67Ile	missense_variant	Exon 2 of 6	1	NM_016127.6	ENSP00000256255.6		Q96BY9-1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251476

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.0000289

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000224

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152322

Hom.:

Cov.:

AF XY:

0.0000805

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.000192

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Bravo

AF:

0.0000416

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.199G>A (p.V67I) alteration is located in exon 2 (coding exon 2) of the SARAF gene. This alteration results from a G to A substitution at nucleotide position 199, causing the valine (V) at amino acid position 67 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.034

T;T;T

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.097

FATHMM_MKL

Benign

0.72

LIST_S2

Uncertain

0.88

D;D;D

M_CAP

Benign

0.0066

MetaRNN

Benign

0.12

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

L;.;.

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.33

N;N;N

REVEL

Benign

0.11

Sift

Benign

0.47

T;T;T

Sift4G

Benign

0.48

T;.;T

Polyphen

0.046

B;.;.

Vest4

0.14

MVP

0.55

MPC

0.079

ClinPred

0.026

GERP RS

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.097

gMVP

0.20

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