6-115943103-T-C

Variant names:

• chr6-115943103-T-C
• NM_002031.3:c.1223A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002031.3(FRK):​c.1223A>G​(p.Asn408Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FRK NM_002031.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.49
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21615723).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRK	NM_002031.3	c.1223A>G	p.Asn408Ser	missense_variant	Exon 7 of 8	ENST00000606080.2	NP_002022.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRK	ENST00000606080.2	c.1223A>G	p.Asn408Ser	missense_variant	Exon 7 of 8	1	NM_002031.3	ENSP00000476145.1
ENSG00000289376	ENST00000692859.3	n.269-40925A>G		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 17, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1223A>G (p.N408S) alteration is located in exon 7 (coding exon 7) of the FRK gene. This alteration results from a A to G substitution at nucleotide position 1223, causing the asparagine (N) at amino acid position 408 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	Benign	0.087
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-0.076
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	0.075	N
PhyloP100		3.5
PrimateAI	Benign	0.39	T
Sift4G	Benign	0.14	T
Polyphen		0.12	B
Vest4		0.26
MutPred		0.51		Gain of disorder (P = 0.0394);
MVP		0.45
MPC		0.18
ClinPred		0.37	T
GERP RS		5.6
Varity_R		0.098
gMVP		0.31
Mutation Taster		=51/49	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

hg19: chr6-116264266;