chrX-32411823-A-G

Variant names:

• chrX-32411823-A-G
• rs28715870
• NM_004006.3:c.4162T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004006.3(DMD):​c.4162T>C​(p.Phe1388Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000898 in 111,382 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. 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. F1388V) has been classified as Benign.

• Frequency: Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 22)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.47
• Publications: 3 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07529187).

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.4162T>C	p.Phe1388Leu	missense	Exon 30 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.4150T>C	p.Phe1384Leu	missense	Exon 30 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.4138T>C	p.Phe1380Leu	missense	Exon 30 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.4162T>C	p.Phe1388Leu	missense	Exon 30 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000378677.6	TSL:5	c.4150T>C	p.Phe1384Leu	missense	Exon 30 of 79	ENSP00000367948.2	P11532-11
	DMD	ENST00000619831.5	TSL:5	c.130T>C	p.Phe44Leu	missense	Exon 2 of 51	ENSP00000479270.2	A0A087WV90

Frequencies

GnomAD3 genomes AF: 0.00000898 AC: 1 AN: 111331 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000327

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00000547 AC: 1 AN: 182914 AF XY: 0.00

Gnomad AFR exome AF: 0.0000760

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: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000898 AC: 1 AN: 111382 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33582

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

African (AFR) AF: 0.0000326 AC: 1 AN: 30636

American (AMR) AF: 0.00 AC: 0 AN: 10445

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2640

East Asian (EAS) AF: 0.00 AC: 0 AN: 3511

South Asian (SAS) AF: 0.00 AC: 0 AN: 2650

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5949

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53129

Other (OTH) AF: 0.00 AC: 0 AN: 1517

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.97
CADD	Benign	13
DANN	Benign	0.87
DEOGEN2	Benign	0.22	T
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.075	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.5
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.021
Sift	Benign	0.24	T
Sift4G	Benign	0.23	T
Polyphen		0.0	B
Vest4		0.049
MutPred		0.24		Gain of disorder (P = 0.0399)
MVP		0.19
MPC		0.016
ClinPred		0.026	T
GERP RS		3.1
PromoterAI		0.026	Neutral
gMVP		0.075
Mutation Taster		=98/2	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: rs28715870; hg19: chrX-32429940;