chrX-151722683-G-A

Variant names:

• chrX-151722683-G-A
• rs747395629
• NM_033085.3:c.476G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_033085.3(FATE1):​c.476G>A​(p.Arg159His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000743 in 1,211,209 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R159S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 1 hem., cov: 24)
  • Exomes 𝑓: 0.0000064 (0 hom. 3 hem.)
• Consequence: FATE1 NM_033085.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0240
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0662958).
• BS2: High Hemizygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FATE1	NM_033085.3	c.476G>A	p.Arg159His	missense_variant	Exon 5 of 5	ENST00000370350.7	NP_149076.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FATE1	ENST00000370350.7	c.476G>A	p.Arg159His	missense_variant	Exon 5 of 5	1	NM_033085.3	ENSP00000359375.3
FATE1	ENST00000417321.1	c.*102G>A		3_prime_UTR_variant	Exon 4 of 4	3		ENSP00000400493.1

Frequencies

GnomAD3 genomes AF: 0.0000176 AC: 2 AN: 113339 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000184

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: 0.00

GnomAD2 exomes AF: 0.0000330 AC: 6 AN: 181888 AF XY: 0.0000299

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000219

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000638 AC: 7 AN: 1097870 Hom.: 0 Cov.: 30 AF XY: 0.00000826 AC XY: 3 AN XY: 363284

African (AFR) AF: 0.00 AC: 0 AN: 26393

American (AMR) AF: 0.000199 AC: 7 AN: 35183

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19373

East Asian (EAS) AF: 0.00 AC: 0 AN: 30201

South Asian (SAS) AF: 0.00 AC: 0 AN: 54107

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40451

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4126

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841955

Other (OTH) AF: 0.00 AC: 0 AN: 46081

GnomAD4 genome AF: 0.0000176 AC: 2 AN: 113339 Hom.: 0 Cov.: 24 AF XY: 0.0000282 AC XY: 1 AN XY: 35469

African (AFR) AF: 0.00 AC: 0 AN: 31267

American (AMR) AF: 0.000184 AC: 2 AN: 10892

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2657

East Asian (EAS) AF: 0.00 AC: 0 AN: 3551

South Asian (SAS) AF: 0.00 AC: 0 AN: 2805

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6361

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53345

Other (OTH) AF: 0.00 AC: 0 AN: 1540

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 24, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.476G>A (p.R159H) alteration is located in exon 5 (coding exon 5) of the FATE1 gene. This alteration results from a G to A substitution at nucleotide position 476, causing the arginine (R) at amino acid position 159 to be replaced by a histidine (H). 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	0.12
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Benign	0.045	T
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.55	T
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.024
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.011
Sift	Benign	0.17	T
Sift4G	Benign	0.22	T
Polyphen		0.41	B
Vest4		0.041
MutPred		0.24		Loss of MoRF binding (P = 0.0232);
MVP		0.78
MPC		0.034
ClinPred		0.048	T
GERP RS		0.47
Varity_R		0.099
gMVP		0.24
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs747395629; hg19: chrX-150891155;