chrX-32345946-G-C

Variant names:

• chrX-32345946-G-C
• rs775837149
• NM_004006.3:c.5583C>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_004006.3(DMD):​c.5583C>G​(p.Leu1861Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000415 in 1,204,892 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts 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. L1861L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000091 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0000037 (0 hom. 3 hem.)
• Consequence: DMD NM_004006.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.79
• 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: 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant X-32345946-G-C is Benign according to our data. Variant chrX-32345946-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2890861.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.79 with no splicing effect.
• BS2: High Hemizygotes in GnomAdExome4 at 3 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMD	NM_004006.3	MANE Select	c.5583C>G	p.Leu1861Leu	synonymous	Exon 39 of 79	NP_003997.2
	DMD	NM_004009.3		c.5571C>G	p.Leu1857Leu	synonymous	Exon 39 of 79	NP_004000.1
	DMD	NM_000109.4		c.5559C>G	p.Leu1853Leu	synonymous	Exon 39 of 79	NP_000100.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMD	ENST00000357033.9	TSL:1 MANE Select	c.5583C>G	p.Leu1861Leu	synonymous	Exon 39 of 79	ENSP00000354923.3
	DMD	ENST00000378677.6	TSL:5	c.5571C>G	p.Leu1857Leu	synonymous	Exon 39 of 79	ENSP00000367948.2
	DMD	ENST00000619831.5	TSL:5	c.1551C>G	p.Leu517Leu	synonymous	Exon 11 of 51	ENSP00000479270.2

Frequencies

GnomAD3 genomes AF: 0.00000914 AC: 1 AN: 109459 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000978

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: 0.00000549 AC: 1 AN: 182095 AF XY: 0.0000149

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: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000365 AC: 4 AN: 1095433 Hom.: 0 Cov.: 30 AF XY: 0.00000829 AC XY: 3 AN XY: 361727

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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

American (AMR) AF: 0.00 AC: 0 AN: 35112

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19309

East Asian (EAS) AF: 0.00 AC: 0 AN: 30029

South Asian (SAS) AF: 0.00 AC: 0 AN: 54067

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40220

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4100

European-Non Finnish (NFE) AF: 0.00000476 AC: 4 AN: 840374

Other (OTH) AF: 0.00 AC: 0 AN: 45920

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000914 AC: 1 AN: 109459 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 32009

African (AFR) AF: 0.00 AC: 0 AN: 30164

American (AMR) AF: 0.0000978 AC: 1 AN: 10226

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2622

East Asian (EAS) AF: 0.00 AC: 0 AN: 3460

South Asian (SAS) AF: 0.00 AC: 0 AN: 2573

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 233

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52442

Other (OTH) AF: 0.00 AC: 0 AN: 1471

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Duchenne muscular dystrophy Benign:1

Dec 31, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	8.8
DANN	Benign	0.81
PhyloP100		1.8
Mutation Taster		=100/0	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: rs775837149; hg19: chrX-32364063;