Variant 1-225847219-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_014698.3(TMEM63A):c.2251-6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00615 in 1,612,192 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0041 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0064 ( 39 hom. )

Consequence

TMEM63A
NM_014698.3 splice_region, intron

Scores

Splicing: ADA: 0.0001691

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: -0.0420

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 links:

TMEM63A (HGNC:):

TMEM63A links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BP6

Variant 1-225847219-A-G is Benign according to our data. Variant chr1-225847219-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2570753.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 623 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM63A	NM_014698.3 linkuse as main transcript	c.2251-6T>C		splice_region_variant, intron_variant		ENST00000366835.8	NP_055513.2	O94886A1NY77

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TMEM63A	ENST00000366835.8 linkuse as main transcript	c.2251-6T>C	splice_region_variant, intron_variant		1	NM_014698.3	ENSP00000355800.3	O94886
TMEM63A	ENST00000496025.1 linkuse as main transcript	n.247T>C	non_coding_transcript_exon_variant	1/2	2
TMEM63A	ENST00000482753.1 linkuse as main transcript	n.331-6T>C	splice_region_variant, intron_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00409

AC:

623

AN:

152266

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00101

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00890

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00625

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00422

AC:

1050

AN:

248728

Hom.:

AF XY:

0.00429

AC XY:

579

AN XY:

134854

show subpopulations

Gnomad AFR exome

AF:

0.000746

Gnomad AMR exome

AF:

0.00670

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.00158

Gnomad NFE exome

AF:

0.00649

Gnomad OTH exome

AF:

0.00775

GnomAD4 exome

AF:

0.00636

AC:

9286

AN:

1459808

Hom.:

Cov.:

AF XY:

0.00615

AC XY:

4463

AN XY:

726058

show subpopulations

Gnomad4 AFR exome

AF:

0.00114

Gnomad4 AMR exome

AF:

0.00680

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00141

Gnomad4 NFE exome

AF:

0.00762

Gnomad4 OTH exome

AF:

0.00650

GnomAD4 genome

AF:

0.00409

AC:

623

AN:

152384

Hom.:

Cov.:

AF XY:

0.00365

AC XY:

272

AN XY:

74526

show subpopulations

Gnomad4 AFR

AF:

0.00101

Gnomad4 AMR

AF:

0.00889

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00113

Gnomad4 NFE

AF:

0.00625

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00478

Hom.:

Bravo

AF:

0.00485

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00633

EpiControl

AF:

0.00581

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2024

TMEM63A: BP4, BS2 -

TMEM63A-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 01, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

6.8

DANN

Benign

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00017

dbscSNV1_RF

Benign

0.030

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over