chr12-69574737-A-T

Variant names:

• chr12-69574737-A-T
• rs777663604
• NM_001278356.2:c.1309A>T

Variant summary

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

The NM_001278356.2(FRS2):​c.1309A>T​(p.Ile437Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I437V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FRS2 NM_001278356.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.32
• Publications: 0 publications found

Genes affected

FRS2 (HGNC:16971): (fibroblast growth factor receptor substrate 2) Enables fibroblast growth factor receptor binding activity and neurotrophin TRKA receptor binding activity. Involved in negative regulation of cardiac muscle cell differentiation. Acts upstream of or within fibroblast growth factor receptor signaling pathway. Located in adherens junction. Biomarker of renal cell carcinoma. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRS2	NM_001278356.2	c.1309A>T	p.Ile437Leu	missense_variant	Exon 9 of 9	ENST00000549921.6	NP_001265285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRS2	ENST00000549921.6	c.1309A>T	p.Ile437Leu	missense_variant	Exon 9 of 9	1	NM_001278356.2	ENSP00000450048.1
FRS2	ENST00000550389.5	c.1309A>T	p.Ile437Leu	missense_variant	Exon 7 of 7	1		ENSP00000447241.1
FRS2	ENST00000397997.6	c.1309A>T	p.Ile437Leu	missense_variant	Exon 7 of 7	5		ENSP00000381083.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461874 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.60	D;D;D
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;.;D
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.66	D;D;D
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.5	M;M;M
PhyloP100		9.3
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.21
Sift	Uncertain	0.0050	D;D;D
Sift4G	Uncertain	0.030	D;D;D
Polyphen		0.90	P;P;P
Vest4		0.73
MutPred		0.54		Gain of catalytic residue at E442 (P = 0.0021);Gain of catalytic residue at E442 (P = 0.0021);Gain of catalytic residue at E442 (P = 0.0021);
MVP		0.65
ClinPred		0.74	D
GERP RS		6.2
Varity_R		0.43
gMVP		0.34
Mutation Taster		=68/32	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs777663604; hg19: chr12-69968517;