1-225849617-C-G

Variant names:

• chr1-225849617-C-G
• rs2292558
• NM_014698.3:c.2071+295G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014698.3(TMEM63A):​c.2071+295G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 152,242 control chromosomes in the GnomAD database, including 934 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 0.10 (934 hom., cov: 32)
• Consequence: TMEM63A NM_014698.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.326
• Publications: 10 publications found

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)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.208 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM63A	NM_014698.3	c.2071+295G>C		intron_variant	Intron 21 of 24	ENST00000366835.8	NP_055513.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM63A	ENST00000366835.8	c.2071+295G>C		intron_variant	Intron 21 of 24	1	NM_014698.3	ENSP00000355800.3

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15868 AN: 152122 Hom.: 933 Cov.: 32

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.0755

Gnomad ASJ AF: 0.0824

Gnomad EAS AF: 0.133

Gnomad SAS AF: 0.219

Gnomad FIN AF: 0.0629

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.107

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.104 AC: 15874 AN: 152242 Hom.: 934 Cov.: 32 AF XY: 0.103 AC XY: 7638 AN XY: 74448

African (AFR) AF: 0.106 AC: 4389 AN: 41518

American (AMR) AF: 0.0754 AC: 1153 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0824 AC: 286 AN: 3472

East Asian (EAS) AF: 0.133 AC: 690 AN: 5172

South Asian (SAS) AF: 0.219 AC: 1057 AN: 4826

European-Finnish (FIN) AF: 0.0629 AC: 668 AN: 10616

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.108 AC: 7321 AN: 68022

Other (OTH) AF: 0.108 AC: 229 AN: 2114

Alfa AF: 0.0535 Hom.: 49

Bravo AF: 0.101

Asia WGS AF: 0.161 AC: 559 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.6
DANN	Benign	0.65
PhyloP100		0.33
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs2292558; hg19: chr1-226037318;