6-116003931-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong

The NM_002031.3(FRK):c.412G>A(p.Gly138Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000103 in 1,460,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: FRK NM_002031.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.14

Genes affected

FRK (HGNC:3955): (fyn related Src family tyrosine kinase) The protein encoded by this gene belongs to the TYR family of protein kinases. This tyrosine kinase is a nuclear protein and may function during G1 and S phase of the cell cycle and suppress growth. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FRK	NM_002031.3	c.412G>A	p.Gly138Ser	missense_variant	2/8	ENST00000606080.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FRK	ENST00000606080.2	c.412G>A	p.Gly138Ser	missense_variant	2/8	1	NM_002031.3	P1
	ENST00000692859.2	n.222+96561G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251014 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135682

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1460748 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 726718

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000990

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 24, 2023

The c.412G>A (p.G138S) alteration is located in exon 2 (coding exon 2) of the FRK gene. This alteration results from a G to A substitution at nucleotide position 412, causing the glycine (G) at amino acid position 138 to be replaced by a serine (S). 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	Pathogenic	0.59
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Uncertain	-0.010
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0094	T
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	-0.014	T
MutationAssessor	Pathogenic	4.0	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.51	T
Sift4G	Uncertain	0.019	D
Polyphen		0.27	B
Vest4		0.85
MutPred		0.88		Gain of disorder (P = 0.0446);
MVP		0.52
MPC		0.43
ClinPred		0.97	D
GERP RS		6.0
Varity_R		0.61
gMVP		0.89

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

Other links and lift over

dbSNP: rs770246096; hg19: chr6-116325094;