6-115944330-G-T

Variant names:

• chr6-115944330-G-T
• rs201586564
• NM_002031.3:c.1054C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PP3_Strong BS2

The NM_002031.3(FRK):​c.1054C>A​(p.His352Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00028 in 1,613,008 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (1 hom.)
• Consequence: FRK NM_002031.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0
• Publications: 4 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.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955
• BS2: High AC in GnomAd4 at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRK	NM_002031.3	c.1054C>A	p.His352Asn	missense_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.1054C>A	p.His352Asn	missense_variant	Exon 6 of 8	1	NM_002031.3	ENSP00000476145.1
ENSG00000289376	ENST00000692859.3	n.269-42152C>A		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.000353

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000112 AC: 28 AN: 251104 AF XY: 0.0000810

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000292 AC: 426 AN: 1460882 Hom.: 1 Cov.: 31 AF XY: 0.000256 AC XY: 186 AN XY: 726760

African (AFR) AF: 0.0000598 AC: 2 AN: 33438

American (AMR) AF: 0.0000672 AC: 3 AN: 44610

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86202

European-Finnish (FIN) AF: 0.000150 AC: 8 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5468

European-Non Finnish (NFE) AF: 0.000357 AC: 397 AN: 1111628

Other (OTH) AF: 0.000265 AC: 16 AN: 60336

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152126 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74322

African (AFR) AF: 0.0000241 AC: 1 AN: 41446

American (AMR) AF: 0.0000655 AC: 1 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000212 Hom.: 0

Bravo AF: 0.000117

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000988 AC: 12

EpiCase AF: 0.000437

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 12, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1054C>A (p.H352N) alteration is located in exon 6 (coding exon 6) of the FRK gene. This alteration results from a C to A substitution at nucleotide position 1054, causing the histidine (H) at amino acid position 352 to be replaced by an asparagine (N). 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	1.0
BayesDel_addAF	Uncertain	0.060	T
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.098	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		10
PrimateAI	Pathogenic	0.86	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.98
MVP		0.84
MPC		0.78
ClinPred		0.96	D
GERP RS		5.8
Varity_R		0.89
gMVP		0.83
Mutation Taster		=25/75	disease causing

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: rs201586564; hg19: chr6-116265493; COSMIC: COSV73384351;