X-32468689-C-G

Variant names:

• chrX-32468689-C-G
• rs72468667
• NM_004006.3:c.2971G>C

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.2971G>C​(p.Glu991Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00201 in 1,208,762 control chromosomes in the GnomAD database, including 1 homozygotes. There are 765 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E991V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., 55 hem., cov: 22)
  • Exomes 𝑓: 0.0021 (1 hom. 710 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 7.01
• Publications: 9 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• 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=0.0083191395).
• BP6: Variant X-32468689-C-G is Benign according to our data. Variant chrX-32468689-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 195752.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 = 0.00147 (164/111423) while in subpopulation NFE AF = 0.00211 (112/53052). AF 95% confidence interval is 0.00179. There are 0 homozygotes in GnomAd4. There are 55 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High AC in GnomAd4 at 164 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.2971G>C	p.Glu991Gln	missense	Exon 23 of 79	NP_003997.2
	DMD	NM_004009.3		c.2959G>C	p.Glu987Gln	missense	Exon 23 of 79	NP_004000.1
	DMD	NM_000109.4		c.2947G>C	p.Glu983Gln	missense	Exon 23 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.2971G>C	p.Glu991Gln	missense	Exon 23 of 79	ENSP00000354923.3
	DMD	ENST00000378677.6	TSL:5	c.2959G>C	p.Glu987Gln	missense	Exon 23 of 79	ENSP00000367948.2
	DMD	ENST00000420596.5	TSL:5	c.94-103490G>C		intron	N/A	ENSP00000399897.1

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 164 AN: 111365 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000293

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00184

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00400

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00211

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00146 AC: 266 AN: 181591 AF XY: 0.00159

Gnomad AFR exome AF: 0.000154

Gnomad AMR exome AF: 0.000513

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00363

Gnomad NFE exome AF: 0.00226

Gnomad OTH exome AF: 0.00224

GnomAD4 exome AF: 0.00207 AC: 2270 AN: 1097339 Hom.: 1 Cov.: 30 AF XY: 0.00196 AC XY: 710 AN XY: 362843

African (AFR) AF: 0.0000758 AC: 2 AN: 26382

American (AMR) AF: 0.000512 AC: 18 AN: 35163

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19372

East Asian (EAS) AF: 0.00 AC: 0 AN: 30159

South Asian (SAS) AF: 0.0000370 AC: 2 AN: 54064

European-Finnish (FIN) AF: 0.00422 AC: 171 AN: 40485

Middle Eastern (MID) AF: 0.000728 AC: 3 AN: 4120

European-Non Finnish (NFE) AF: 0.00237 AC: 1993 AN: 841550

Other (OTH) AF: 0.00176 AC: 81 AN: 46044

GnomAD4 genome AF: 0.00147 AC: 164 AN: 111423 Hom.: 0 Cov.: 22 AF XY: 0.00163 AC XY: 55 AN XY: 33643

African (AFR) AF: 0.000293 AC: 9 AN: 30762

American (AMR) AF: 0.00183 AC: 19 AN: 10362

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2644

East Asian (EAS) AF: 0.00 AC: 0 AN: 3539

South Asian (SAS) AF: 0.00 AC: 0 AN: 2653

European-Finnish (FIN) AF: 0.00400 AC: 24 AN: 6001

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.00211 AC: 112 AN: 53052

Other (OTH) AF: 0.00 AC: 0 AN: 1508

Alfa AF: 0.00172 Hom.: 37

Bravo AF: 0.00137

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00138 AC: 4

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00223 AC: 15

ExAC AF: 0.00157 AC: 191

EpiCase AF: 0.00241

EpiControl AF: 0.00340

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	not provided (4)
-	-	1	Cardiovascular phenotype (1)
-	-	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	0.10
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.0083	T
MetaSVM	Benign	-0.94	T
PhyloP100		7.0
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.067
Sift	Benign	0.16	T
Sift4G	Benign	0.098	T
Polyphen		0.92	P
Vest4		0.44
MVP		0.67
MPC		0.020
ClinPred		0.048	T
GERP RS		5.1
gMVP		0.12
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs72468667; hg19: chrX-32486806;