Genetic Variant TMEM63A:c.*671T>C (chr1-225846268-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.*671T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 152,606 control chromosomes in the GnomAD database, including 1,007 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 0.11 ( 1004 hom., cov: 33)

Exomes 𝑓: 0.098 ( 3 hom. )

Consequence

TMEM63A
NM_014698.3 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.700

Publications

14 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:

ENSG00000242861 (HGNC:):

ENSG00000242861 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=-0.81).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.231 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM63A	NM_014698.3 link	c.*671T>C		3_prime_UTR_variant	Exon 25 of 25	ENST00000366835.8	NP_055513.2	O94886A1NY77

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM63A	ENST00000366835.8 link	c.*671T>C		3_prime_UTR_variant	Exon 25 of 25	1	NM_014698.3	ENSP00000355800.3		O94886
ENSG00000242861	ENST00000424332.1 link	n.43+212T>C		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes

AF:

0.107

AC:

16258

AN:

152192

Hom.:

1002

Cov.:

show subpopulations

Gnomad AFR

AF:

0.110

Gnomad AMI

AF:

0.0570

Gnomad AMR

AF:

0.0758

Gnomad ASJ

AF:

0.0862

Gnomad EAS

AF:

0.139

Gnomad SAS

AF:

0.242

Gnomad FIN

AF:

0.0626

Gnomad MID

AF:

0.111

Gnomad NFE

AF:

0.109

Gnomad OTH

AF:

0.109

GnomAD4 exome

AF:

0.0980

AC:

AN:

296

Hom.:

Cov.:

AF XY:

0.113

AC XY:

AN XY:

212

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.500

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.115

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0992

AC:

AN:

242

Other (OTH)

AF:

0.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.566

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.107

AC:

16270

AN:

152310

Hom.:

1004

Cov.:

AF XY:

0.105

AC XY:

7839

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.110

AC:

4554

AN:

41580

American (AMR)

AF:

0.0757

AC:

1158

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0862

AC:

299

AN:

3468

East Asian (EAS)

AF:

0.139

AC:

721

AN:

5180

South Asian (SAS)

AF:

0.243

AC:

1173

AN:

4830

European-Finnish (FIN)

AF:

0.0626

AC:

665

AN:

10618

Middle Eastern (MID)

AF:

0.105

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.109

AC:

7383

AN:

68012

Other (OTH)

AF:

0.111

AC:

234

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

754

1508

2263

3017

3771

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

198

396

594

792

990

<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:

0.108

Hom.:

4000

Bravo

AF:

0.103

Asia WGS

AF:

0.169

AC:

588

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.17

(source)

DANN

Benign

0.75

PhyloP100

-0.70

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over