Genetic Variant TMEM63A:c.2188-54T>C (chr1-225848608-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_014698.3(TMEM63A):c.2188-54T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.612 in 1,579,976 control chromosomes in the GnomAD database, including 298,732 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.65 ( 32516 hom., cov: 32)

Exomes 𝑓: 0.61 ( 266216 hom. )

Consequence

TMEM63A
NM_014698.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.20

Publications

29 publications found

Variant links:

Genes affected

TMEM63A (HGNC:29118): (transmembrane protein 63A) Enables mechanosensitive ion channel activity. Predicted to be involved in cation transmembrane transport. Located in centriolar satellite and lysosomal membrane. Implicated in hypomyelinating leukodystrophy. [provided by Alliance of Genome Resources, Apr 2022]

TMEM63A Gene-Disease associations (from GenCC):

leukodystrophy, hypomyelinating, 19, transient infantile
Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

TMEM63A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.771 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014698.3. 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
	TMEM63A	NM_014698.3	MANE Select	c.2188-54T>C		intron	N/A	NP_055513.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM63A	ENST00000366835.8	TSL:1 MANE Select	c.2188-54T>C		intron	N/A	ENSP00000355800.3
	TMEM63A	ENST00000482753.1	TSL:3	n.93-54T>C		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.646

AC:

98061

AN:

151894

Hom.:

32468

Cov.:

show subpopulations

Gnomad AFR

AF:

0.778

Gnomad AMI

AF:

0.353

Gnomad AMR

AF:

0.575

Gnomad ASJ

AF:

0.541

Gnomad EAS

AF:

0.695

Gnomad SAS

AF:

0.703

Gnomad FIN

AF:

0.509

Gnomad MID

AF:

0.509

Gnomad NFE

AF:

0.604

Gnomad OTH

AF:

0.636

GnomAD4 exome

AF:

0.609

AC:

868916

AN:

1427964

Hom.:

266216

AF XY:

0.611

AC XY:

435200

AN XY:

712460

show subpopulations

African (AFR)

AF:

0.789

AC:

25912

AN:

32828

American (AMR)

AF:

0.531

AC:

23513

AN:

44288

Ashkenazi Jewish (ASJ)

AF:

0.543

AC:

14071

AN:

25922

East Asian (EAS)

AF:

0.661

AC:

26136

AN:

39526

South Asian (SAS)

AF:

0.692

AC:

59141

AN:

85498

European-Finnish (FIN)

AF:

0.523

AC:

26339

AN:

50328

Middle Eastern (MID)

AF:

0.543

AC:

3085

AN:

5686

European-Non Finnish (NFE)

AF:

0.603

AC:

654119

AN:

1084650

Other (OTH)

AF:

0.618

AC:

36600

AN:

59238

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

16943

33886

50829

67772

84715

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17650

35300

52950

70600

88250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.646

AC:

98164

AN:

152012

Hom.:

32516

Cov.:

AF XY:

0.639

AC XY:

47498

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.779

AC:

32282

AN:

41462

American (AMR)

AF:

0.575

AC:

8774

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.541

AC:

1876

AN:

3468

East Asian (EAS)

AF:

0.694

AC:

3586

AN:

5170

South Asian (SAS)

AF:

0.701

AC:

3373

AN:

4810

European-Finnish (FIN)

AF:

0.509

AC:

5376

AN:

10552

Middle Eastern (MID)

AF:

0.510

AC:

150

AN:

294

European-Non Finnish (NFE)

AF:

0.604

AC:

41085

AN:

67976

Other (OTH)

AF:

0.638

AC:

1340

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1734

3468

5203

6937

8671

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

792

1584

2376

3168

3960

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.617

Hom.:

26720

Bravo

AF:

0.652

Asia WGS

AF:

0.724

AC:

2517

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.15

(source)

DANN

Benign

0.68

PhyloP100

-2.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over