rs145064612

Variant names:

• chrX-32697907-G-A
• rs145064612
• NM_004006.3:c.923C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-32697907-G-A
• chrX-32697907-G-T
• chrX-32697907-G-C

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.923C>T​(p.Thr308Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000277 in 1,207,837 control chromosomes in the GnomAD database, including 2 homozygotes. There are 205 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T308N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 2 hem., cov: 22)
  • Exomes 𝑓: 0.00030 (2 hom. 203 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.82
• Publications: 2 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0063116252).
• BP6: Variant X-32697907-G-A is Benign according to our data. Variant chrX-32697907-G-A is described in ClinVar as Benign. ClinVar VariationId is 289521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000301 (330/1097168) while in subpopulation SAS AF = 0.0058 (313/53957). AF 95% confidence interval is 0.00527. There are 2 homozygotes in GnomAdExome4. There are 203 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 330 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.923C>T	p.Thr308Ile	missense	Exon 9 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.911C>T	p.Thr304Ile	missense	Exon 9 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.899C>T	p.Thr300Ile	missense	Exon 9 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.923C>T	p.Thr308Ile	missense	Exon 9 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000288447.9	TSL:1	c.899C>T	p.Thr300Ile	missense	Exon 9 of 18	ENSP00000288447.4	Q4G0X0
	DMD	ENST00000447523.1	TSL:1	c.247-124061C>T		intron	N/A	ENSP00000395904.1	Q14174

Frequencies

GnomAD3 genomes AF: 0.0000271 AC: 3 AN: 110613 Hom.: 0 Cov.: 22

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: 0.00115

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000657 AC: 119 AN: 181050 AF XY: 0.00108

Gnomad AFR exome AF: 0.0000768

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: 0.000224

GnomAD4 exome AF: 0.000301 AC: 330 AN: 1097168 Hom.: 2 Cov.: 30 AF XY: 0.000560 AC XY: 203 AN XY: 362756

African (AFR) AF: 0.0000379 AC: 1 AN: 26370

American (AMR) AF: 0.00 AC: 0 AN: 35102

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19353

East Asian (EAS) AF: 0.00 AC: 0 AN: 30163

South Asian (SAS) AF: 0.00580 AC: 313 AN: 53957

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40482

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4134

European-Non Finnish (NFE) AF: 0.00000594 AC: 5 AN: 841552

Other (OTH) AF: 0.000217 AC: 10 AN: 46055

GnomAD4 genome AF: 0.0000361 AC: 4 AN: 110669 Hom.: 0 Cov.: 22 AF XY: 0.0000607 AC XY: 2 AN XY: 32937

African (AFR) AF: 0.00 AC: 0 AN: 30442

American (AMR) AF: 0.00 AC: 0 AN: 10318

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2624

East Asian (EAS) AF: 0.00 AC: 0 AN: 3477

South Asian (SAS) AF: 0.00154 AC: 4 AN: 2604

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5948

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52848

Other (OTH) AF: 0.00 AC: 0 AN: 1510

Alfa AF: 0.0000868 Hom.: 1

Bravo AF: 0.0000416

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000346 AC: 1

ExAC AF: 0.000651 AC: 79

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	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	0.15
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.0063	T
MetaSVM	Benign	-0.81	T
PhyloP100		2.8
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.088
Sift	Benign	0.092	T
Sift4G	Benign	0.20	T
Polyphen		0.0	B
Vest4		0.23
MutPred		0.29		Loss of glycosylation at T308 (P = 0.0211)
MVP		0.50
MPC		0.017
ClinPred		0.040	T
GERP RS		5.1
gMVP		0.32
Mutation Taster		=98/2	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: rs145064612; hg19: chrX-32716024;