6-115944425-T-C

Variant names:

• chr6-115944425-T-C
• rs139630641
• NM_002031.3:c.959A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_002031.3(FRK):​c.959A>G​(p.Asn320Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000245 in 1,592,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: FRK NM_002031.3 missense, splice_region
• Scores: Splicing: ADA: 0.00002029
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.22
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08159953).
• BP6: Variant 6-115944425-T-C is Benign according to our data. Variant chr6-115944425-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3517176.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRK	NM_002031.3	c.959A>G	p.Asn320Ser	missense_variant, splice_region_variant	Exon 6 of 8	ENST00000606080.2	NP_002022.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRK	ENST00000606080.2	c.959A>G	p.Asn320Ser	missense_variant, splice_region_variant	Exon 6 of 8	1	NM_002031.3	ENSP00000476145.1
ENSG00000289376	ENST00000692859.3	n.269-42247A>G		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000507

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000303 AC: 7 AN: 231368 AF XY: 0.0000160

Gnomad AFR exome AF: 0.000378

Gnomad AMR exome AF: 0.00

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: 0.0000125 AC: 18 AN: 1440508 Hom.: 0 Cov.: 30 AF XY: 0.00000698 AC XY: 5 AN XY: 716044

African (AFR) AF: 0.000434 AC: 14 AN: 32240

American (AMR) AF: 0.00 AC: 0 AN: 38484

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24952

East Asian (EAS) AF: 0.00 AC: 0 AN: 39574

South Asian (SAS) AF: 0.0000122 AC: 1 AN: 82230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53090

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4838

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1105654

Other (OTH) AF: 0.0000336 AC: 2 AN: 59446

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74324

African (AFR) AF: 0.000507 AC: 21 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000727 Hom.: 0

Bravo AF: 0.000125

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.0000547

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Nov 21, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	12
DANN	Benign	0.17
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.78
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.082	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.28	N
PhyloP100		3.2
PrimateAI	Benign	0.39	T
Sift4G	Benign	1.0	T
Polyphen		0.68	P
Vest4		0.13
MVP		0.37
MPC		0.18
ClinPred		0.057	T
GERP RS		1.8
Varity_R		0.035
gMVP		0.11
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000020
dbscSNV1_RF	Benign	0.010
SpliceAI score (max)		0.010		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: rs139630641; hg19: chr6-116265588;