rs16990264

Variant names:

• chrX-32365029-A-T
• rs16990264
• NM_004006.3:c.5016T>A

Your query was ambiguous. Multiple possible variants found:

• chrX-32365029-A-T
• chrX-32365029-A-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004006.3(DMD):​c.5016T>A​(p.Asn1672Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00388 in 1,208,793 control chromosomes in the GnomAD database, including 95 homozygotes. There are 1,291 hemizygotes in GnomAD. In-silico tool predicts 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. N1672I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.020 (54 hom., 576 hem., cov: 22)
  • Exomes 𝑓: 0.0023 (41 hom. 715 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.179
• Publications: 6 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0073643923).
• BP6: Variant X-32365029-A-T is Benign according to our data. Variant chrX-32365029-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0635 is higher than 0.05.

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.5016T>A	p.Asn1672Lys	missense	Exon 35 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.5004T>A	p.Asn1668Lys	missense	Exon 35 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.4992T>A	p.Asn1664Lys	missense	Exon 35 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.5016T>A	p.Asn1672Lys	missense	Exon 35 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000378677.6	TSL:5	c.5004T>A	p.Asn1668Lys	missense	Exon 35 of 79	ENSP00000367948.2	P11532-11
	DMD	ENST00000619831.5	TSL:5	c.984T>A	p.Asn328Lys	missense	Exon 7 of 51	ENSP00000479270.2	A0A087WV90

Frequencies

GnomAD3 genomes AF: 0.0195 AC: 2165 AN: 110989 Hom.: 53 Cov.: 22

Gnomad AFR AF: 0.0655

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0110

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00226

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00420

Gnomad NFE AF: 0.000415

Gnomad OTH AF: 0.0161

GnomAD2 exomes AF: 0.00610 AC: 1117 AN: 183125 AF XY: 0.00446

Gnomad AFR exome AF: 0.0710

Gnomad AMR exome AF: 0.00467

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000257

Gnomad OTH exome AF: 0.00376

GnomAD4 exome AF: 0.00228 AC: 2506 AN: 1097753 Hom.: 41 Cov.: 30 AF XY: 0.00197 AC XY: 715 AN XY: 363243

African (AFR) AF: 0.0683 AC: 1802 AN: 26379

American (AMR) AF: 0.00546 AC: 192 AN: 35196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19374

East Asian (EAS) AF: 0.00 AC: 0 AN: 30163

South Asian (SAS) AF: 0.00102 AC: 55 AN: 54139

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40520

Middle Eastern (MID) AF: 0.00411 AC: 17 AN: 4132

European-Non Finnish (NFE) AF: 0.000233 AC: 196 AN: 841775

Other (OTH) AF: 0.00530 AC: 244 AN: 46075

GnomAD4 genome AF: 0.0196 AC: 2179 AN: 111040 Hom.: 54 Cov.: 22 AF XY: 0.0173 AC XY: 576 AN XY: 33230

African (AFR) AF: 0.0659 AC: 2014 AN: 30556

American (AMR) AF: 0.0109 AC: 113 AN: 10357

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2638

East Asian (EAS) AF: 0.00 AC: 0 AN: 3524

South Asian (SAS) AF: 0.00189 AC: 5 AN: 2641

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5900

Middle Eastern (MID) AF: 0.00459 AC: 1 AN: 218

European-Non Finnish (NFE) AF: 0.000415 AC: 22 AN: 53014

Other (OTH) AF: 0.0159 AC: 24 AN: 1506

Alfa AF: 0.00325 Hom.: 58

Bravo AF: 0.0225

ESP6500AA AF: 0.0673 AC: 258

ESP6500EA AF: 0.000743 AC: 5

ExAC AF: 0.00685 AC: 831

EpiCase AF: 0.000327

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	2	Dilated cardiomyopathy 3B (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Duchenne muscular dystrophy (1)
-	-	1	Duchenne muscular dystrophy;C0878544:Cardiomyopathy;C0917713:Becker muscular dystrophy;na:Dystrophin deficiency (1)
-	-	1	Duchenne muscular dystrophy;C0917713:Becker muscular dystrophy;C3668940:Dilated cardiomyopathy 3B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	11
DANN	Uncertain	0.98
DEOGEN2	Benign	0.31	T
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0074	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.18
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.066
Sift	Uncertain	0.016	D
Sift4G	Benign	0.25	T
Polyphen		0.25	B
Vest4		0.22
MutPred		0.65		Gain of ubiquitination at N1672 (P = 0.017)
MVP		0.66
MPC		0.056
ClinPred		0.027	T
GERP RS		-0.67
gMVP		0.16
Mutation Taster		=90/10	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

Other links and lift over

dbSNP: rs16990264; hg19: chrX-32383146;