Genetic Variant SAYSD1:p.Glu70Lys (chr6-39105776-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018322.3(SAYSD1):c.208G>A(p.Glu70Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000891 in 1,458,928 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

SAYSD1
NM_018322.3 missense, splice_region

Scores

Splicing: ADA: 0.9993

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.51

Variant links:

Genes affected

SAYSD1 (HGNC:21025): (SAYSVFN motif domain containing 1) Located in intracellular membrane-bounded organelle. [provided by Alliance of Genome Resources, Apr 2022]

SAYSD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SAYSD1	NM_018322.3 link	c.208G>A	p.Glu70Lys	missense_variant, splice_region_variant	Exon 2 of 2	ENST00000229903.5	NP_060792.1	Q9NPB0-1
SAYSD1	NM_001304793.2 link	c.7G>A	p.Glu3Lys	missense_variant, splice_region_variant	Exon 3 of 3		NP_001291722.1	Q9NPB0-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SAYSD1	ENST00000229903.5 link	c.208G>A	p.Glu70Lys	missense_variant, splice_region_variant	Exon 2 of 2	1	NM_018322.3	ENSP00000229903.4		Q9NPB0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249366

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134790

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:

0.00000889

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000891

AC:

AN:

1458928

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

725444

show subpopulations

Gnomad4 AFR exome

AF:

0.000240

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:

9.01e-7

Gnomad4 OTH exome

AF:

0.0000664

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000721

Hom.:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 06, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.208G>A (p.E70K) alteration is located in exon 2 (coding exon 2) of the SAYSD1 gene. This alteration results from a G to A substitution at nucleotide position 208, causing the glutamic acid (E) at amino acid position 70 to be replaced by a lysine (K). 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

0.091

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.014

.;T

Eigen

Benign

0.12

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.52

T;T

M_CAP

Benign

0.0024

MetaRNN

Benign

0.12

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.9

.;L

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.79

N;N

REVEL

Benign

0.087

Sift

Benign

0.071

T;T

Sift4G

Benign

0.26

T;T

Polyphen

0.46

.;P

Vest4

0.11

MutPred

0.31

.;Gain of ubiquitination at E70 (P = 0.0066);

MVP

0.088

MPC

0.13

ClinPred

0.36

GERP RS

5.8

Varity_R

0.16

gMVP

0.31

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.010

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