4-190025956-G-A

Variant names:

• chr4-190025956-G-A
• NM_001286820.2:c.445C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001286820.2(FRG2):​c.445C>T​(p.His149Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FRG2 NM_001286820.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.328

Genes affected

FRG2 (HGNC:19136): (FSHD region gene 2) Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.060276777).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRG2	NM_001286820.2	c.445C>T	p.His149Tyr	missense_variant	Exon 4 of 4	ENST00000504750.6	NP_001273749.1
FRG2	NM_001005217.4	c.442C>T	p.His148Tyr	missense_variant	Exon 4 of 4		NP_001005217.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRG2	ENST00000504750.6	c.445C>T	p.His149Tyr	missense_variant	Exon 4 of 4	1	NM_001286820.2	ENSP00000424015.1
FRG2	ENST00000378763.1	c.442C>T	p.His148Tyr	missense_variant	Exon 4 of 4	1		ENSP00000368039.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461670 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727146

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.442C>T (p.H148Y) alteration is located in exon 4 (coding exon 4) of the FRG2 gene. This alteration results from a C to T substitution at nucleotide position 442, causing the histidine (H) at amino acid position 148 to be replaced by a tyrosine (Y). 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	0.098
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.14
DANN	Benign	0.63
DEOGEN2	Benign	0.012	.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0034	N
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.060	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.55	.;N
PROVEAN	Benign	-0.75	N;N
REVEL	Benign	0.037
Sift	Benign	0.30	T;T
Sift4G	Benign	0.48	T;T
Polyphen		0.036	.;B
Vest4		0.14
MutPred		0.18		.;Gain of glycosylation at T153 (P = 0.0737);
MVP		0.014
MPC		2.1
ClinPred		0.21	T
GERP RS		0.35
Varity_R		0.054
gMVP		0.0028

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-190947111; COSMIC: COSV66459924; COSMIC: COSV66459924;