X-31478281-T-C

Variant names:

• chrX-31478281-T-C
• rs1800279
• NM_004006.3:c.8762A>G
• DMD p.His2921Arg

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004006.3(DMD):​c.8762A>G​(p.His2921Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0282 in 1,209,039 control chromosomes in the GnomAD database, including 345 homozygotes. There are 11,312 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. H2921H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.022 (24 hom., 722 hem., cov: 22)
  • Exomes 𝑓: 0.029 (321 hom. 10590 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:19
• Conservation: PhyloP100: 1.61
• Publications: 15 publications found

Genes affected

DMD (HGNC:2928): (dystrophin) This gene spans a genomic range of greater than 2 Mb and encodes a large protein containing an N-terminal actin-binding domain and multiple spectrin repeats. The encoded protein forms a component of the dystrophin-glycoprotein complex (DGC), which bridges the inner cytoskeleton and the extracellular matrix. Deletions, duplications, and point mutations at this gene locus may cause Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), or cardiomyopathy. Alternative promoter usage and alternative splicing result in numerous distinct transcript variants and protein isoforms for this gene. [provided by RefSeq, Dec 2016]

DMD Gene-Disease associations (from GenCC):

• Becker muscular dystrophy

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• dilated cardiomyopathy 3B

  Inheritance: XL Classification: DEFINITIVE Submitted by: Ambry Genetics
• Duchenne and Becker muscular dystrophy

  Inheritance: XL Classification: DEFINITIVE Submitted by: Myriad Women's Health
• Duchenne muscular dystrophy

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• progressive muscular dystrophy

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• symptomatic form of muscular dystrophy of Duchenne and Becker in female carriers

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015792578).
• BP6: Variant X-31478281-T-C is Benign according to our data. Variant chrX-31478281-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 11269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.022 (2442/110875) while in subpopulation NFE AF = 0.032 (1696/52924). AF 95% confidence interval is 0.0308. There are 24 homozygotes in GnomAd4. There are 722 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2442 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004006.3. 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
	DMD	NM_004006.3	MANE Select	c.8762A>G	p.His2921Arg	missense	Exon 59 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.8750A>G	p.His2917Arg	missense	Exon 59 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.8738A>G	p.His2913Arg	missense	Exon 59 of 79	NP_000100.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMD	ENST00000357033.9	TSL:1 MANE Select	c.8762A>G	p.His2921Arg	missense	Exon 59 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000378677.6	TSL:5	c.8750A>G	p.His2917Arg	missense	Exon 59 of 79	ENSP00000367948.2	P11532-11
	DMD	ENST00000619831.5	TSL:5	c.4730A>G	p.His1577Arg	missense	Exon 31 of 51	ENSP00000479270.2	A0A087WV90

Frequencies

GnomAD3 genomes AF: 0.0220 AC: 2443 AN: 110823 Hom.: 24 Cov.: 22

Gnomad AFR AF: 0.00371

Gnomad AMI AF: 0.00146

Gnomad AMR AF: 0.0176

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0260

Gnomad FIN AF: 0.0501

Gnomad MID AF: 0.0254

Gnomad NFE AF: 0.0320

Gnomad OTH AF: 0.0223

GnomAD2 exomes AF: 0.0256 AC: 4685 AN: 183282 AF XY: 0.0262

Gnomad AFR exome AF: 0.00365

Gnomad AMR exome AF: 0.0154

Gnomad ASJ exome AF: 0.0226

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0419

Gnomad NFE exome AF: 0.0329

Gnomad OTH exome AF: 0.0325

GnomAD4 exome AF: 0.0289 AC: 31713 AN: 1098164 Hom.: 321 Cov.: 34 AF XY: 0.0291 AC XY: 10590 AN XY: 363528

African (AFR) AF: 0.00394 AC: 104 AN: 26401

American (AMR) AF: 0.0156 AC: 549 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.0213 AC: 413 AN: 19386

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30206

South Asian (SAS) AF: 0.0317 AC: 1718 AN: 54146

European-Finnish (FIN) AF: 0.0444 AC: 1801 AN: 40530

Middle Eastern (MID) AF: 0.0413 AC: 171 AN: 4136

European-Non Finnish (NFE) AF: 0.0305 AC: 25698 AN: 842058

Other (OTH) AF: 0.0273 AC: 1258 AN: 46097

GnomAD4 genome AF: 0.0220 AC: 2442 AN: 110875 Hom.: 24 Cov.: 22 AF XY: 0.0218 AC XY: 722 AN XY: 33115

African (AFR) AF: 0.00370 AC: 113 AN: 30553

American (AMR) AF: 0.0175 AC: 181 AN: 10361

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 50 AN: 2638

East Asian (EAS) AF: 0.00 AC: 0 AN: 3543

South Asian (SAS) AF: 0.0261 AC: 67 AN: 2564

European-Finnish (FIN) AF: 0.0501 AC: 295 AN: 5890

Middle Eastern (MID) AF: 0.0279 AC: 6 AN: 215

European-Non Finnish (NFE) AF: 0.0320 AC: 1696 AN: 52924

Other (OTH) AF: 0.0220 AC: 33 AN: 1502

Alfa AF: 0.0281 Hom.: 1496

Bravo AF: 0.0193

EpiCase AF: 0.0336

EpiControl AF: 0.0315

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	3	not provided (3)
-	-	2	Duchenne muscular dystrophy (2)
-	1	-	Becker muscular dystrophy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 3B (1)
-	-	1	DMD-related disorder (1)
-	-	1	Duchenne muscular dystrophy;C0878544:Cardiomyopathy;C0917713:Becker muscular dystrophy;na:Dystrophin deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	9.5
DANN	Benign	0.70
DEOGEN2	Benign	0.22	T
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-0.99	T
PhyloP100		1.6
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.75	N
REVEL	Benign	0.050
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
gMVP		0.23
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1800279;

hg19: chrX-31496398;

COSMIC: COSV58889263;