rs16998350

Variant names:

• chrX-32545184-T-A
• rs16998350
• NM_004006.3:c.2143A>T

Your query was ambiguous. Multiple possible variants found:

• chrX-32545184-T-A
• chrX-32545184-T-G

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.2143A>T​(p.Thr715Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,209,230 control chromosomes in the GnomAD database, including 15 homozygotes. There are 355 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/18 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. T715P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0055 (7 hom., 175 hem., cov: 23)
  • Exomes 𝑓: 0.00063 (8 hom. 180 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 0.661
• Publications: 2 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=0.0054530203).
• BP6: Variant X-32545184-T-A is Benign according to our data. Variant chrX-32545184-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00555 (621/111960) while in subpopulation AFR AF = 0.0194 (597/30852). AF 95% confidence interval is 0.0181. There are 7 homozygotes in GnomAd4. There are 175 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 621 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.2143A>T	p.Thr715Ser	missense	Exon 17 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.2131A>T	p.Thr711Ser	missense	Exon 17 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.2119A>T	p.Thr707Ser	missense	Exon 17 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.2143A>T	p.Thr715Ser	missense	Exon 17 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000288447.9	TSL:1	c.2119A>T	p.Thr707Ser	missense	Exon 17 of 18	ENSP00000288447.4	Q4G0X0
	DMD	ENST00000378677.6	TSL:5	c.2131A>T	p.Thr711Ser	missense	Exon 17 of 79	ENSP00000367948.2	P11532-11

Frequencies

GnomAD3 genomes AF: 0.00557 AC: 623 AN: 111908 Hom.: 7 Cov.: 23

Gnomad AFR AF: 0.0195

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

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: 0.0000752

Gnomad OTH AF: 0.00465

GnomAD2 exomes AF: 0.00171 AC: 313 AN: 182707 AF XY: 0.00117

Gnomad AFR exome AF: 0.0199

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000614

Gnomad OTH exome AF: 0.00178

GnomAD4 exome AF: 0.000632 AC: 693 AN: 1097270 Hom.: 8 Cov.: 31 AF XY: 0.000496 AC XY: 180 AN XY: 362840

African (AFR) AF: 0.0196 AC: 517 AN: 26360

American (AMR) AF: 0.00128 AC: 45 AN: 35177

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19365

East Asian (EAS) AF: 0.00 AC: 0 AN: 30193

South Asian (SAS) AF: 0.00 AC: 0 AN: 54122

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40496

Middle Eastern (MID) AF: 0.000243 AC: 1 AN: 4110

European-Non Finnish (NFE) AF: 0.0000879 AC: 74 AN: 841404

Other (OTH) AF: 0.00122 AC: 56 AN: 46043

GnomAD4 genome AF: 0.00555 AC: 621 AN: 111960 Hom.: 7 Cov.: 23 AF XY: 0.00512 AC XY: 175 AN XY: 34154

African (AFR) AF: 0.0194 AC: 597 AN: 30852

American (AMR) AF: 0.00124 AC: 13 AN: 10513

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2642

East Asian (EAS) AF: 0.00 AC: 0 AN: 3549

South Asian (SAS) AF: 0.00 AC: 0 AN: 2701

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6109

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.0000752 AC: 4 AN: 53166

Other (OTH) AF: 0.00459 AC: 7 AN: 1525

Alfa AF: 0.000304 Hom.: 1

Bravo AF: 0.00635

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0149 AC: 57

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.00183 AC: 222

EpiCase AF: 0.000273

EpiControl AF: 0.0000594

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	4	not provided (4)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 3B (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	0.11
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	15
DANN	Benign	0.93
DEOGEN2	Benign	0.22	T
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.66
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.031
Sift	Benign	0.41	T
Sift4G	Benign	0.40	T
Polyphen		0.0030	B
Vest4		0.11
MutPred		0.26		Loss of methylation at K710 (P = 0.0847)
MVP		0.54
MPC		0.015
ClinPred		0.0034	T
GERP RS		0.10
gMVP		0.11
Mutation Taster		=99/1	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: rs16998350; hg19: chrX-32563301;