dbSNP rs3738051: TMEM63A:c.1634+105T>C (chr1-225855773-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.1634+105T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0467 in 1,155,110 control chromosomes in the GnomAD database, including 1,727 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 0.042 ( 206 hom., cov: 32)

Exomes 𝑓: 0.047 ( 1521 hom. )

Consequence

TMEM63A
NM_014698.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.20

Publications

1 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=-0.82).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.14 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.1634+105T>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.1634+105T>C		intron	N/A	ENSP00000355800.3

Frequencies

GnomAD3 genomes

AF:

0.0414

AC:

6302

AN:

152196

Hom.:

200

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0128

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0466

Gnomad ASJ

AF:

0.0634

Gnomad EAS

AF:

0.149

Gnomad SAS

AF:

0.0772

Gnomad FIN

AF:

0.0813

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0401

Gnomad OTH

AF:

0.0458

GnomAD4 exome

AF:

0.0475

AC:

47592

AN:

1002796

Hom.:

1521

AF XY:

0.0482

AC XY:

24418

AN XY:

506940

show subpopulations

African (AFR)

AF:

0.0120

AC:

270

AN:

22464

American (AMR)

AF:

0.0573

AC:

1450

AN:

25284

Ashkenazi Jewish (ASJ)

AF:

0.0573

AC:

1109

AN:

19370

East Asian (EAS)

AF:

0.152

AC:

5264

AN:

34636

South Asian (SAS)

AF:

0.0770

AC:

4910

AN:

63726

European-Finnish (FIN)

AF:

0.0793

AC:

3840

AN:

48454

Middle Eastern (MID)

AF:

0.0533

AC:

222

AN:

4168

European-Non Finnish (NFE)

AF:

0.0382

AC:

28312

AN:

740304

Other (OTH)

AF:

0.0499

AC:

2215

AN:

44390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

2174

4348

6523

8697

10871

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1030

2060

3090

4120

5150

<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:

0.0416

AC:

6336

AN:

152314

Hom.:

206

Cov.:

AF XY:

0.0437

AC XY:

3256

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.0133

AC:

553

AN:

41576

American (AMR)

AF:

0.0468

AC:

716

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0634

AC:

220

AN:

3468

East Asian (EAS)

AF:

0.149

AC:

770

AN:

5178

South Asian (SAS)

AF:

0.0774

AC:

374

AN:

4830

European-Finnish (FIN)

AF:

0.0813

AC:

864

AN:

10622

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0401

AC:

2727

AN:

68014

Other (OTH)

AF:

0.0506

AC:

107

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

305

611

916

1222

1527

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

172

258

344

430

<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:

0.0385

Hom.:

Bravo

AF:

0.0376

Asia WGS

AF:

0.133

AC:

461

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.0080

(source)

DANN

Benign

0.52

PhyloP100

-2.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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