4-190174726-T-A

Position:

• chr4-190174726-T-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001306068.3(DUX4):​c.953T>A​(p.Val318Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 6/7 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.096 (8 hom., cov: 24)
  • Exomes 𝑓: 0.068 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: DUX4 NM_001306068.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.04

Genes affected

DUX4 (HGNC:50800): (double homeobox 4) This gene is located within a D4Z4 repeat array in the subtelomeric region of chromosome 4q. The D4Z4 repeat is polymorphic in length; a similar D4Z4 repeat array has been identified on chromosome 10. Each D4Z4 repeat unit has an open reading frame (named DUX4) that encodes two homeoboxes; the repeat-array and ORF is conserved in other mammals. The encoded protein has been reported to function as a transcriptional activator of paired-like homeodomain transcription factor 1 (PITX1; GeneID 5307). Contraction of the macrosatellite repeat causes autosomal dominant facioscapulohumeral muscular dystrophy (FSHD). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

DUX4 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11159688).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DUX4	NM_001306068.3	c.953T>A	p.Val318Asp	missense_variant	1/2	ENST00000565211.1	NP_001292997.1
DUX4	NM_001293798.3	c.953T>A	p.Val318Asp	missense_variant	1/3		NP_001280727.1
DUX4	NM_001363820.2	c.478-467T>A		intron_variant			NP_001350749.1
DUX4	NR_137167.1	n.953T>A		non_coding_transcript_exon_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DUX4	ENST00000565211.1	c.953T>A	p.Val318Asp	missense_variant	1/2	1	NM_001306068.3	ENSP00000458065.1
DUX4	ENST00000569241.5	c.953T>A	p.Val318Asp	missense_variant	1/3	1		ENSP00000456539.1
DUX4	ENST00000570263.5	c.478-467T>A		intron_variant		1		ENSP00000455112.1
DUX4	ENST00000616166.1	c.953T>A	p.Val318Asp	missense_variant	1/1	6		ENSP00000483555.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 11251 AN: 117578 Hom.: 8 Cov.: 24 FAILED QC

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.0498

Gnomad AMR AF: 0.0878

Gnomad ASJ AF: 0.0946

Gnomad EAS AF: 0.0386

Gnomad SAS AF: 0.0666

Gnomad FIN AF: 0.0446

Gnomad MID AF: 0.103

Gnomad NFE AF: 0.0768

Gnomad OTH AF: 0.0849

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0683 AC: 18404 AN: 269596 Hom.: 2 Cov.: 0 AF XY: 0.0683 AC XY: 9677 AN XY: 141720

Gnomad4 AFR exome AF: 0.151

Gnomad4 AMR exome AF: 0.0688

Gnomad4 ASJ exome AF: 0.0846

Gnomad4 EAS exome AF: 0.0216

Gnomad4 SAS exome AF: 0.0702

Gnomad4 FIN exome AF: 0.0409

Gnomad4 NFE exome AF: 0.0723

Gnomad4 OTH exome AF: 0.0751

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0957 AC: 11259 AN: 117648 Hom.: 8 Cov.: 24 AF XY: 0.0940 AC XY: 5326 AN XY: 56678

Gnomad4 AFR AF: 0.147

Gnomad4 AMR AF: 0.0878

Gnomad4 ASJ AF: 0.0946

Gnomad4 EAS AF: 0.0390

Gnomad4 SAS AF: 0.0664

Gnomad4 FIN AF: 0.0446

Gnomad4 NFE AF: 0.0768

Gnomad4 OTH AF: 0.0841

Alfa AF: 0.0860 Hom.: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
CADD	Benign	19
DEOGEN2	Benign	0.028	T;T;T
MetaRNN	Benign	0.11	T;T;T
PROVEAN	Benign	-0.85	.;N;N
Sift	Uncertain	0.0090	.;D;D
Sift4G	Uncertain	0.022	D;D;D
Vest4		0.19
gMVP		0.17

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1415001972; hg19: chrUn_gl000228-113557;