1-225847219-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_014698.3(TMEM63A):c.2251-6T>C variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001691
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0420

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]

ACMG classification

Verdict is Benign. Variant got -16 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_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 623 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM63A	NM_014698.3	c.2251-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000366835.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM63A	ENST00000366835.8	c.2251-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_014698.3	P1
TMEM63A	ENST00000496025.1	n.247T>C		non_coding_transcript_exon_variant	1/2	2
TMEM63A	ENST00000482753.1	n.331-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00409 AC: 623 AN: 152266 Hom.: 0 Cov.: 33

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.: 6 AF XY: 0.00429 AC XY: 579 AN XY: 134854

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.: 39 Cov.: 31 AF XY: 0.00615 AC XY: 4463 AN XY: 726058

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.: 0 Cov.: 33 AF XY: 0.00365 AC XY: 272 AN XY: 74526

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.: 0

Bravo AF: 0.00485

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00633

EpiControl AF: 0.00581

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

TMEM63A: BP4, BS2 -

TMEM63A-related disorder Benign:1

Likely benign, criteria provided, single submitter

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

Other links and lift over

dbSNP: rs12121252; hg19: chr1-226034920;