1-225862909-C-A

Variant names:

• chr1-225862909-C-A
• rs10158985
• NM_014698.3:c.747-58G>T

Variant summary

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

The NM_014698.3(TMEM63A):​c.747-58G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.206 in 1,519,338 control chromosomes in the GnomAD database, including 34,298 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 0.17 (2494 hom., cov: 30)
  • Exomes 𝑓: 0.21 (31804 hom.)
• Consequence: TMEM63A NM_014698.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.04
• Publications: 9 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=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.225 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM63A	NM_014698.3	c.747-58G>T		intron_variant	Intron 10 of 24	ENST00000366835.8	NP_055513.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM63A	ENST00000366835.8	c.747-58G>T		intron_variant	Intron 10 of 24	1	NM_014698.3	ENSP00000355800.3
TMEM63A	ENST00000537914.5	c.-232-58G>T		intron_variant	Intron 3 of 6	1		ENSP00000445237.1
TMEM63A	ENST00000474478.5	n.2456G>T		non_coding_transcript_exon_variant	Exon 2 of 4	2
TMEM63A	ENST00000483779.1	n.515-58G>T		intron_variant	Intron 1 of 2	2

Frequencies

GnomAD3 genomes AF: 0.167 AC: 25324 AN: 151644 Hom.: 2496 Cov.: 30

Gnomad AFR AF: 0.0865

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.00561

Gnomad SAS AF: 0.111

Gnomad FIN AF: 0.216

Gnomad MID AF: 0.131

Gnomad NFE AF: 0.228

Gnomad OTH AF: 0.181

GnomAD4 exome AF: 0.210 AC: 287107 AN: 1367576 Hom.: 31804 Cov.: 22 AF XY: 0.208 AC XY: 141720 AN XY: 681122

African (AFR) AF: 0.0797 AC: 2496 AN: 31332

American (AMR) AF: 0.116 AC: 4535 AN: 39264

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 4532 AN: 25058

East Asian (EAS) AF: 0.00266 AC: 100 AN: 37530

South Asian (SAS) AF: 0.119 AC: 9625 AN: 81030

European-Finnish (FIN) AF: 0.228 AC: 11712 AN: 51260

Middle Eastern (MID) AF: 0.151 AC: 850 AN: 5622

European-Non Finnish (NFE) AF: 0.233 AC: 242254 AN: 1039324

Other (OTH) AF: 0.193 AC: 11003 AN: 57156

GnomAD4 genome AF: 0.167 AC: 25307 AN: 151762 Hom.: 2494 Cov.: 30 AF XY: 0.164 AC XY: 12140 AN XY: 74132

African (AFR) AF: 0.0863 AC: 3567 AN: 41348

American (AMR) AF: 0.151 AC: 2306 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 605 AN: 3466

East Asian (EAS) AF: 0.00524 AC: 27 AN: 5156

South Asian (SAS) AF: 0.110 AC: 528 AN: 4810

European-Finnish (FIN) AF: 0.216 AC: 2277 AN: 10518

Middle Eastern (MID) AF: 0.127 AC: 37 AN: 292

European-Non Finnish (NFE) AF: 0.228 AC: 15462 AN: 67918

Other (OTH) AF: 0.179 AC: 377 AN: 2102

Alfa AF: 0.201 Hom.: 4382

Bravo AF: 0.159

Asia WGS AF: 0.0630 AC: 221 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.038
DANN	Benign	0.83
PhyloP100		-2.0
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: rs10158985; hg19: chr1-226050609; COSMIC: COSV64764467; COSMIC: COSV64764467;