chrX-32390175-G-T

Variant names:

• chrX-32390175-G-T
• rs863224997
• NM_004006.3:c.4240C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004006.3(DMD):​c.4240C>A​(p.Gln1414Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,075,112 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1414R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000019 (0 hom. 1 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.84
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3	c.4240C>A	p.Gln1414Lys	missense_variant	Exon 31 of 79	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9	c.4240C>A	p.Gln1414Lys	missense_variant	Exon 31 of 79	1	NM_004006.3	ENSP00000354923.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000186 AC: 2 AN: 1075112 Hom.: 0 Cov.: 27 AF XY: 0.00000292 AC XY: 1 AN XY: 341952

African (AFR) AF: 0.00 AC: 0 AN: 25974

American (AMR) AF: 0.00 AC: 0 AN: 35171

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19237

East Asian (EAS) AF: 0.00 AC: 0 AN: 30011

South Asian (SAS) AF: 0.00 AC: 0 AN: 53535

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40422

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4075

European-Non Finnish (NFE) AF: 0.00000244 AC: 2 AN: 821333

Other (OTH) AF: 0.00 AC: 0 AN: 45354

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	.;T;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;.;D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Uncertain	0.61	D;D;D;D
MetaSVM	Benign	-1.2	T
PhyloP100		6.8
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.8	.;N;.;N
REVEL	Benign	0.19
Sift	Benign	0.093	.;T;.;T
Sift4G	Benign	0.29	T;T;T;T
Polyphen		0.90	.;P;.;.
Vest4		0.63
MutPred		0.41		.;.;Gain of ubiquitination at Q1414 (P = 0.0077);Gain of ubiquitination at Q1414 (P = 0.0077);
MVP		0.70
MPC		0.032
ClinPred		0.68	D
GERP RS		5.8
gMVP		0.25
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs863224997; hg19: chrX-32408292;