4-189953126-G-T

Variant names:

• chr4-189953126-G-T
• rs770433406
• NM_004477.3:c.317+1G>T

Variant summary

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

The NM_004477.3(FRG1):​c.317+1G>T variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FRG1 NM_004477.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 8.83
• Publications: 5 publications found

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

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

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004477.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRG1	NM_004477.3	MANE Select	c.317+1G>T		splice_donor intron	N/A	NP_004468.1	Q14331

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRG1	ENST00000226798.9	TSL:1 MANE Select	c.317+1G>T		splice_donor intron	N/A	ENSP00000226798.4	Q14331
	FRG1	ENST00000896233.1		c.317+1G>T		splice_donor intron	N/A	ENSP00000566292.1
	FRG1	ENST00000940554.1		c.317+1G>T		splice_donor intron	N/A	ENSP00000610613.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0224 AC: 3741 AN: 166990 AF XY: 0.0198

Gnomad AFR exome AF: 0.0342

Gnomad AMR exome AF: 0.0456

Gnomad ASJ exome AF: 0.0157

Gnomad EAS exome AF: 0.0430

Gnomad FIN exome AF: 0.00355

Gnomad NFE exome AF: 0.0171

Gnomad OTH exome AF: 0.0376

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.109 Hom.: 0

ExAC AF: 0.00194 AC: 233

ClinVar

ClinVar submissions

Significance: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	CIC-rearranged sarcoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		8.8
GERP RS		3.5
Mutation Taster		=23/77	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs770433406; hg19: chr4-190874281; COSMIC: COSV57002318;