rs360093

Variant names:

• chr1-225877045-G-T
• rs360093
• NM_014698.3:c.186+350C>A

Variant summary

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

The NM_014698.3(TMEM63A):​c.186+350C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.573 in 151,930 control chromosomes in the GnomAD database, including 26,822 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 0.57 (26822 hom., cov: 31)
• Consequence: TMEM63A NM_014698.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.822
• Publications: 4 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=-0.97).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.666 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM63A	NM_014698.3	c.186+350C>A		intron_variant	Intron 3 of 24	ENST00000366835.8	NP_055513.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM63A	ENST00000366835.8	c.186+350C>A		intron_variant	Intron 3 of 24	1	NM_014698.3	ENSP00000355800.3
TMEM63A	ENST00000436966.1	c.186+350C>A		intron_variant	Intron 1 of 3	2		ENSP00000409002.1
TMEM63A	ENST00000487817.1	n.100+350C>A		intron_variant	Intron 1 of 2	2

Frequencies

GnomAD3 genomes AF: 0.573 AC: 86981 AN: 151812 Hom.: 26811 Cov.: 31

Gnomad AFR AF: 0.336

Gnomad AMI AF: 0.774

Gnomad AMR AF: 0.630

Gnomad ASJ AF: 0.719

Gnomad EAS AF: 0.466

Gnomad SAS AF: 0.511

Gnomad FIN AF: 0.794

Gnomad MID AF: 0.658

Gnomad NFE AF: 0.671

Gnomad OTH AF: 0.602

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

GnomAD4 genome AF: 0.573 AC: 87010 AN: 151930 Hom.: 26822 Cov.: 31 AF XY: 0.578 AC XY: 42932 AN XY: 74232

African (AFR) AF: 0.336 AC: 13912 AN: 41420

American (AMR) AF: 0.630 AC: 9616 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.719 AC: 2494 AN: 3470

East Asian (EAS) AF: 0.466 AC: 2407 AN: 5162

South Asian (SAS) AF: 0.511 AC: 2458 AN: 4810

European-Finnish (FIN) AF: 0.794 AC: 8376 AN: 10548

Middle Eastern (MID) AF: 0.653 AC: 192 AN: 294

European-Non Finnish (NFE) AF: 0.671 AC: 45585 AN: 67952

Other (OTH) AF: 0.602 AC: 1267 AN: 2106

Alfa AF: 0.613 Hom.: 5086

Bravo AF: 0.554

Asia WGS AF: 0.475 AC: 1652 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.088
DANN	Benign	0.80
PhyloP100		-0.82
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs360093; hg19: chr1-226064745;