4-189960757-T-G

Variant names:

• chr4-189960757-T-G
• NM_004477.3:c.547T>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004477.3(FRG1):​c.547T>G​(p.Cys183Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000688 in 1,453,446 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: FRG1 NM_004477.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.07

Genes affected

FRG1 (HGNC:3954): (FSHD region gene 1) This gene maps to a location 100 kb centromeric of the repeat units on chromosome 4q35 which are deleted in facioscapulohumeral muscular dystrophy (FSHD). It is evolutionarily conserved and has related sequences on multiple human chromosomes but DNA sequence analysis did not reveal any homology to known genes. In vivo studies demonstrate the encoded protein is localized to the nucleolus. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 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
FRG1	NM_004477.3	c.547T>G	p.Cys183Gly	missense_variant	Exon 7 of 9	ENST00000226798.9	NP_004468.1
FRG1	XM_017007958.2	c.163T>G	p.Cys55Gly	missense_variant	Exon 3 of 5		XP_016863447.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRG1	ENST00000226798.9	c.547T>G	p.Cys183Gly	missense_variant	Exon 7 of 9	1	NM_004477.3	ENSP00000226798.4
FRG1	ENST00000524583.5	c.163T>G	p.Cys55Gly	missense_variant	Exon 6 of 7	5		ENSP00000435067.1
FRG1	ENST00000507103.1	n.10T>G		non_coding_transcript_exon_variant	Exon 1 of 4	3		ENSP00000462603.1
FRG1	ENST00000514482.1	n.524-105T>G		intron_variant	Intron 6 of 6	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453446 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 723130

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: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.547T>G (p.C183G) alteration is located in exon 7 (coding exon 7) of the FRG1 gene. This alteration results from a T to G substitution at nucleotide position 547, causing the cysteine (C) at amino acid position 183 to be replaced by a glycine (G). 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	0.21
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	23
DANN	Benign	0.94
DEOGEN2	Benign	0.30	T;.
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Benign	0.025	D
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Benign	-0.95	T
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.5	D;D
REVEL	Benign	0.20
Sift	Benign	0.34	T;T
Sift4G	Benign	0.55	T;T
Polyphen		0.81	P;.
Vest4		0.60
MutPred		0.42		Loss of methylation at K179 (P = 0.1212);.;
MVP		0.68
MPC		0.84
ClinPred		0.93	D
GERP RS		4.0
Varity_R		0.90
gMVP		0.38

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: chr4-190881912;