6-115967680-C-T

Variant names:

• chr6-115967680-C-T
• rs555269385
• NM_002031.3:c.670G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_002031.3(FRK):​c.670G>A​(p.Val224Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,610,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: FRK NM_002031.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.64
• Publications: 1 publications found

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]

ENSG00000289376 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.40437162).
• BS2: High AC in GnomAdExome4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRK	NM_002031.3	c.670G>A	p.Val224Met	missense_variant	Exon 4 of 8	ENST00000606080.2	NP_002022.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRK	ENST00000606080.2	c.670G>A	p.Val224Met	missense_variant	Exon 4 of 8	1	NM_002031.3	ENSP00000476145.1
ENSG00000289376	ENST00000692859.3	n.269-65502G>A		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.0000266 AC: 4 AN: 150586 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000245

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: 0.0000442

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000319 AC: 8 AN: 251064 AF XY: 0.0000368

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000871

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1460144 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 726300

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.0000448 AC: 2 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26074

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39670

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86070

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1110834

Other (OTH) AF: 0.0000166 AC: 1 AN: 60276

GnomAD4 genome AF: 0.0000265 AC: 4 AN: 150700 Hom.: 0 Cov.: 32 AF XY: 0.0000273 AC XY: 2 AN XY: 73386

African (AFR) AF: 0.0000244 AC: 1 AN: 40974

American (AMR) AF: 0.00 AC: 0 AN: 15096

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5132

South Asian (SAS) AF: 0.00 AC: 0 AN: 4786

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10080

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67876

Other (OTH) AF: 0.00 AC: 0 AN: 2096

Alfa AF: 0.0000298 Hom.: 0

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.670G>A (p.V224M) alteration is located in exon 4 (coding exon 4) of the FRK gene. This alteration results from a G to A substitution at nucleotide position 670, causing the valine (V) at amino acid position 224 to be replaced by a methionine (M). 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	0.13
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.6
PrimateAI	Benign	0.47	T
Sift4G	Benign	0.13	T
Polyphen		0.99	D
Vest4		0.49
MutPred		0.40		Gain of ubiquitination at K222 (P = 0.1079);
MVP		0.48
MPC		0.59
ClinPred		0.81	D
GERP RS		5.4
Varity_R		0.10
gMVP		0.56
Mutation Taster		=69/31	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: rs555269385; hg19: chr6-116288843; COSMIC: COSV73384289;