rs960307751

Variant names:

• chrX-32697953-T-C
• rs960307751
• NM_004006.3:c.877A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Moderate BP6_Moderate BS2_Supporting

The NM_004006.3(DMD):​c.877A>G​(p.Lys293Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000999 in 1,201,764 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 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. K293K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000091 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.000010 (0 hom. 4 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 2.32
• Publications: 0 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: Ambry Genetics, Orphanet
• 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, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2357651).
• BP6: Variant X-32697953-T-C is Benign according to our data. Variant chrX-32697953-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 526095.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 11 XL,AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.877A>G	p.Lys293Glu	missense	Exon 9 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.865A>G	p.Lys289Glu	missense	Exon 9 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.853A>G	p.Lys285Glu	missense	Exon 9 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.877A>G	p.Lys293Glu	missense	Exon 9 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000288447.9	TSL:1	c.853A>G	p.Lys285Glu	missense	Exon 9 of 18	ENSP00000288447.4	Q4G0X0
	DMD	ENST00000447523.1	TSL:1	c.247-124107A>G		intron	N/A	ENSP00000395904.1	Q14174

Frequencies

GnomAD3 genomes AF: 0.00000914 AC: 1 AN: 109369 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000334

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000116 AC: 2 AN: 171730 AF XY: 0.0000173

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000757

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.0000101 AC: 11 AN: 1092395 Hom.: 0 Cov.: 30 AF XY: 0.0000112 AC XY: 4 AN XY: 358531

African (AFR) AF: 0.00 AC: 0 AN: 26302

American (AMR) AF: 0.000173 AC: 6 AN: 34597

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19269

East Asian (EAS) AF: 0.00 AC: 0 AN: 30022

South Asian (SAS) AF: 0.00 AC: 0 AN: 53087

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40222

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4123

European-Non Finnish (NFE) AF: 0.00000596 AC: 5 AN: 838891

Other (OTH) AF: 0.00 AC: 0 AN: 45882

GnomAD4 genome AF: 0.00000914 AC: 1 AN: 109369 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 31743

African (AFR) AF: 0.0000334 AC: 1 AN: 29929

American (AMR) AF: 0.00 AC: 0 AN: 10164

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2618

East Asian (EAS) AF: 0.00 AC: 0 AN: 3447

South Asian (SAS) AF: 0.00 AC: 0 AN: 2544

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5787

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52480

Other (OTH) AF: 0.00 AC: 0 AN: 1481

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.0000302

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Duchenne muscular dystrophy (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	0.12
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.86	T
PhyloP100		2.3
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.030
Sift	Benign	0.15	T
Sift4G	Uncertain	0.026	D
Polyphen		0.010	B
Vest4		0.46
MutPred		0.35		Loss of MoRF binding (P = 0.0118)
MVP		0.68
MPC		0.018
ClinPred		0.15	T
GERP RS		3.3
gMVP		0.33
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs960307751; hg19: chrX-32716070;