rs2288648

Positions:

• chr7-151077221-G-A
• chr7-151077221-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006712.5(FASTK):​c.1307C>T​(p.Ala436Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0136 in 1,612,612 control chromosomes in the GnomAD database, including 1,458 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A436T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.037 (313 hom., cov: 34)
  • Exomes 𝑓: 0.011 (1145 hom.)
• Consequence: FASTK NM_006712.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.461

Genes affected

FASTK (HGNC:24676): (Fas activated serine/threonine kinase) The protein encoded by this gene is a member of the serine/threonine protein kinase family. This kinase was shown to be activated rapidly during Fas-mediated apoptosis in Jurkat cells. In response to Fas receptor ligation, it phosphorylates TIA1, an apoptosis-promoting nuclear RNA-binding protein. The encoded protein is a strong inducer of lymphocyte apoptosis. Two transcript variants encoding different isoforms have been found for this gene. Other variants exist, but their full-length natures have not yet been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012855828).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FASTK	NM_006712.5	c.1307C>T	p.Ala436Val	missense_variant	8/10	ENST00000297532.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FASTK	ENST00000297532.11	c.1307C>T	p.Ala436Val	missense_variant	8/10	1	NM_006712.5	P1

Frequencies

GnomAD3 genomes AF: 0.0374 AC: 5688 AN: 152196 Hom.: 315 Cov.: 34

Gnomad AFR AF: 0.0974

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0283

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.194

Gnomad SAS AF: 0.0106

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00124

Gnomad OTH AF: 0.0330

GnomAD3 exomes AF: 0.0291 AC: 7191 AN: 247120 Hom.: 482 AF XY: 0.0248 AC XY: 3316 AN XY: 133960

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.0445

Gnomad ASJ exome AF: 0.00162

Gnomad EAS exome AF: 0.195

Gnomad SAS exome AF: 0.00737

Gnomad FIN exome AF: 0.000466

Gnomad NFE exome AF: 0.00124

Gnomad OTH exome AF: 0.0157

GnomAD4 exome AF: 0.0111 AC: 16226 AN: 1460298 Hom.: 1145 Cov.: 33 AF XY: 0.0105 AC XY: 7649 AN XY: 726388

Gnomad4 AFR exome AF: 0.0984

Gnomad4 AMR exome AF: 0.0431

Gnomad4 ASJ exome AF: 0.00111

Gnomad4 EAS exome AF: 0.207

Gnomad4 SAS exome AF: 0.00728

Gnomad4 FIN exome AF: 0.000380

Gnomad4 NFE exome AF: 0.000794

Gnomad4 OTH exome AF: 0.0184

GnomAD4 genome AF: 0.0374 AC: 5693 AN: 152314 Hom.: 313 Cov.: 34 AF XY: 0.0373 AC XY: 2776 AN XY: 74472

Gnomad4 AFR AF: 0.0973

Gnomad4 AMR AF: 0.0284

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.193

Gnomad4 SAS AF: 0.0106

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00124

Gnomad4 OTH AF: 0.0321

Alfa AF: 0.00973 Hom.: 85

Bravo AF: 0.0434

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0899 AC: 396

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.0288 AC: 3495

Asia WGS AF: 0.0830 AC: 287 AN: 3478

EpiCase AF: 0.00147

EpiControl AF: 0.00166

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.034
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	6.1
DANN	Benign	0.81
DEOGEN2	Benign	0.044	.;.;T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.10	T;T;T;T
MetaRNN	Benign	0.0013	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	.;.;N;.
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	1.9	.;N;N;N
REVEL	Benign	0.062
Sift	Benign	0.66	.;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	.;.;B;.
Vest4		0.042
MPC		0.60
ClinPred		0.0018	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.024
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs2288648; hg19: chr7-150774308; COSMIC: COSV52540892; COSMIC: COSV52540892;