X-32454698-A-G

Variant names:

• chrX-32454698-A-G
• rs370685748
• NM_004006.3:c.3567T>C

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_004006.3(DMD):​c.3567T>C​(p.Thr1189Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. 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. T1189T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000010 (0 hom., 0 hem., cov: 20)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: DMD NM_004006.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.910
• Publications: 0 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant X-32454698-A-G is Benign according to our data. Variant chrX-32454698-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1598454.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.91 with no splicing effect.

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.3567T>C	p.Thr1189Thr	synonymous	Exon 26 of 79	NP_003997.2
	DMD	NM_004009.3		c.3555T>C	p.Thr1185Thr	synonymous	Exon 26 of 79	NP_004000.1
	DMD	NM_000109.4		c.3543T>C	p.Thr1181Thr	synonymous	Exon 26 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.3567T>C	p.Thr1189Thr	synonymous	Exon 26 of 79	ENSP00000354923.3
	DMD	ENST00000378677.6	TSL:5	c.3555T>C	p.Thr1185Thr	synonymous	Exon 26 of 79	ENSP00000367948.2
	DMD	ENST00000682899.1		n.3774T>C		non_coding_transcript_exon	Exon 26 of 27

Frequencies

GnomAD3 genomes AF: 0.0000101 AC: 1 AN: 98762 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000112

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

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1081849 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 352379

African (AFR) AF: 0.00 AC: 0 AN: 26042

American (AMR) AF: 0.00 AC: 0 AN: 34717

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19030

East Asian (EAS) AF: 0.00 AC: 0 AN: 29756

South Asian (SAS) AF: 0.00 AC: 0 AN: 51956

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37455

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4066

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 833434

Other (OTH) AF: 0.00 AC: 0 AN: 45393

GnomAD4 genome AF: 0.0000101 AC: 1 AN: 98789 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 25319

African (AFR) AF: 0.00 AC: 0 AN: 27232

American (AMR) AF: 0.000112 AC: 1 AN: 8896

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2468

East Asian (EAS) AF: 0.00 AC: 0 AN: 3119

South Asian (SAS) AF: 0.00 AC: 0 AN: 2168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4170

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 193

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 48574

Other (OTH) AF: 0.00 AC: 0 AN: 1331

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Duchenne muscular dystrophy Benign:1

Jun 02, 2024

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	-0.77
CADD	Benign	6.3
DANN	Benign	0.64
PhyloP100		-0.91

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: rs370685748; hg19: chrX-32472815;