4-189961863-G-A

Variant names:

• chr4-189961863-G-A
• rs1296533233
• NM_004477.3:c.671G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004477.3(FRG1):​c.671G>A​(p.Ser224Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000277 in 1,444,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: FRG1 NM_004477.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.55

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10877496).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FRG1	NM_004477.3	c.671G>A	p.Ser224Asn	missense_variant	Exon 8 of 9	ENST00000226798.9	NP_004468.1
FRG1	XM_017007958.2	c.287G>A	p.Ser96Asn	missense_variant	Exon 4 of 5		XP_016863447.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FRG1	ENST00000226798.9	c.671G>A	p.Ser224Asn	missense_variant	Exon 8 of 9	1	NM_004477.3	ENSP00000226798.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000419 AC: 1 AN: 238584 Hom.: 0 AF XY: 0.00000771 AC XY: 1 AN XY: 129718

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000570

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000277 AC: 4 AN: 1444166 Hom.: 0 Cov.: 27 AF XY: 0.00000278 AC XY: 2 AN XY: 718170

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000510

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 19, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.671G>A (p.S224N) alteration is located in exon 8 (coding exon 8) of the FRG1 gene. This alteration results from a G to A substitution at nucleotide position 671, causing the serine (S) at amino acid position 224 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	Uncertain	0.37
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	20
DANN	Benign	0.60
DEOGEN2	Benign	0.054	T;.
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.48
FATHMM_MKL	Uncertain	0.82	D
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	0.11	N;N
REVEL	Benign	0.083
Sift	Benign	0.74	T;T
Sift4G	Benign	0.66	T;T
Polyphen		0.028	B;.
Vest4		0.26
MutPred		0.33		Loss of phosphorylation at S224 (P = 0.0208);.;
MVP		0.35
MPC		0.30
ClinPred		0.069	T
GERP RS		3.0
Varity_R		0.31
gMVP		0.047

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

Publications

LitVar

Other links and lift over

dbSNP: rs1296533233; hg19: chr4-190883018;