chrX-32491330-G-A

Variant names:

• chrX-32491330-G-A
• rs552275776
• NM_004006.3:c.2569C>T

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.2569C>T​(p.Pro857Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000461 in 1,209,669 control chromosomes in the GnomAD database, including 4 homozygotes. There are 296 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P857L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., 14 hem., cov: 24)
  • Exomes 𝑓: 0.00049 (4 hom. 282 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.42
• Publications: 1 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

ENSG00000297605 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.007158637).
• BP6: Variant X-32491330-G-A is Benign according to our data. Variant chrX-32491330-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227307.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000206 (23/111839) while in subpopulation SAS AF = 0.00856 (23/2687). AF 95% confidence interval is 0.00585. There are 0 homozygotes in GnomAd4. There are 14 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High AC in GnomAd4 at 23 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.2569C>T	p.Pro857Ser	missense	Exon 20 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.2557C>T	p.Pro853Ser	missense	Exon 20 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.2545C>T	p.Pro849Ser	missense	Exon 20 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.2569C>T	p.Pro857Ser	missense	Exon 20 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000378677.6	TSL:5	c.2557C>T	p.Pro853Ser	missense	Exon 20 of 79	ENSP00000367948.2	P11532-11
	DMD	ENST00000420596.5	TSL:5	c.94-126131C>T		intron	N/A	ENSP00000399897.1	Q14172

Frequencies

GnomAD3 genomes AF: 0.000206 AC: 23 AN: 111784 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00854

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00107 AC: 197 AN: 183490 AF XY: 0.00147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.000441

GnomAD4 exome AF: 0.000487 AC: 535 AN: 1097830 Hom.: 4 Cov.: 30 AF XY: 0.000776 AC XY: 282 AN XY: 363202

African (AFR) AF: 0.00 AC: 0 AN: 26397

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19377

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30195

South Asian (SAS) AF: 0.00940 AC: 509 AN: 54137

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40528

Middle Eastern (MID) AF: 0.00145 AC: 6 AN: 4136

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841777

Other (OTH) AF: 0.000391 AC: 18 AN: 46076

GnomAD4 genome AF: 0.000206 AC: 23 AN: 111839 Hom.: 0 Cov.: 24 AF XY: 0.000412 AC XY: 14 AN XY: 34013

African (AFR) AF: 0.00 AC: 0 AN: 30762

American (AMR) AF: 0.00 AC: 0 AN: 10521

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3561

South Asian (SAS) AF: 0.00856 AC: 23 AN: 2687

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6009

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53230

Other (OTH) AF: 0.00 AC: 0 AN: 1519

Alfa AF: 0.000104 Hom.: 1

Bravo AF: 0.0000604

ExAC AF: 0.00124 AC: 151

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	DMD-related disorder (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	0.083
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.89
CADD	Benign	17
DANN	Benign	0.15
DEOGEN2	Benign	0.23	T
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0072	T
MetaSVM	Benign	-1.1	T
PhyloP100		3.4
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.051
Sift	Benign	0.61	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.24
MutPred		0.35		Loss of catalytic residue at P857 (P = 0.0384)
MVP		0.31
MPC		0.049
ClinPred		0.018	T
GERP RS		2.9
gMVP		0.064
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

Other links and lift over

dbSNP: rs552275776; hg19: chrX-32509447;