Genetic Variant NM_033085.3:c.93C>A (chrX-151716212-C-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_033085.3(FATE1):c.93C>A(p.His31Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000249 in 1,165,618 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 13 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000026 ( 0 hom. 12 hem. )

Consequence

FATE1
NM_033085.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -3.01

Variant links:

Genes affected

FATE1 (HGNC:24683): (fetal and adult testis expressed 1) This gene encodes a cancer-testis antigen that is highly expressed in hepatocellular carcinomas and other tumors and weakly expressed in normal tissues except testis. The protein is strongly expressed in spermatogonia, primary spermatocytes, and Sertoli cells in seminiferous tubules. This protein may have a role in the control of early testicular differentiation and cell proliferation. [provided by RefSeq, Jan 2010]

FATE1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0507482).

BS2

High Hemizygotes in GnomAdExome4 at 12 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FATE1	NM_033085.3 link	c.93C>A	p.His31Gln	missense_variant	Exon 1 of 5	ENST00000370350.7	NP_149076.1	Q969F0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FATE1	ENST00000370350.7 link	c.93C>A	p.His31Gln	missense_variant	Exon 1 of 5	1	NM_033085.3	ENSP00000359375.3		Q969F0
FATE1	ENST00000417321.1 link	c.69C>A	p.His23Gln	missense_variant	Exon 1 of 4	3		ENSP00000400493.1		H7C1I5

Frequencies

GnomAD3 genomes

AF:

0.0000178

AC:

AN:

112378

Hom.:

Cov.:

AF XY:

0.0000290

AC XY:

AN XY:

34526

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000376

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000872

AC:

AN:

114639

Hom.:

AF XY:

0.00

AC XY:

AN XY:

40477

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:

0.0000225

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000256

AC:

AN:

1053240

Hom.:

Cov.:

AF XY:

0.0000349

AC XY:

AN XY:

344048

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:

0.0000318

Gnomad4 OTH exome

AF:

0.0000225

GnomAD4 genome

AF:

0.0000178

AC:

AN:

112378

Hom.:

Cov.:

AF XY:

0.0000290

AC XY:

AN XY:

34526

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000376

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000540

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 13, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.93C>A (p.H31Q) alteration is located in exon 1 (coding exon 1) of the FATE1 gene. This alteration results from a C to A substitution at nucleotide position 93, causing the histidine (H) at amino acid position 31 to be replaced by a glutamine (Q). 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

0.19

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.0030

DANN

Benign

0.88

DEOGEN2

Benign

0.010

T;T

FATHMM_MKL

Benign

0.0082

LIST_S2

Benign

0.32

T;T

M_CAP

Benign

0.0030

MetaRNN

Benign

0.051

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.83

L;.

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.74

N;D

REVEL

Benign

0.037

Sift

Benign

0.38

T;T

Sift4G

Benign

0.52

T;T

Polyphen

0.0090

B;.

Vest4

0.054

MutPred

0.13

Gain of helix (P = 0.0854);.;

MVP

0.85

MPC

0.023

ClinPred

0.058

GERP RS

-8.4

Varity_R

0.059

gMVP

0.073

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