chr1-225852703-C-T

Variant names:

• chr1-225852703-C-T
• rs1009668
• NM_014698.3:c.1864G>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.1864G>A​(p.Val622Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,613,466 control chromosomes in the GnomAD database, including 10,960 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V622L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.094 (1007 hom., cov: 33)
  • Exomes 𝑓: 0.11 (9953 hom.)
• Consequence: TMEM63A NM_014698.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.39
• Publications: 40 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, Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0011433959).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.175 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014698.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM63A	NM_014698.3	MANE Select	c.1864G>A	p.Val622Met	missense	Exon 20 of 25	NP_055513.2	O94886

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM63A	ENST00000366835.8	TSL:1 MANE Select	c.1864G>A	p.Val622Met	missense	Exon 20 of 25	ENSP00000355800.3	O94886
	TMEM63A	ENST00000954243.1		c.1864G>A	p.Val622Met	missense	Exon 19 of 24	ENSP00000624302.1
	TMEM63A	ENST00000900923.1		c.1912G>A	p.Val638Met	missense	Exon 20 of 25	ENSP00000570982.1

Frequencies

GnomAD3 genomes AF: 0.0941 AC: 14308 AN: 152084 Hom.: 1005 Cov.: 33

Gnomad AFR AF: 0.0231

Gnomad AMI AF: 0.222

Gnomad AMR AF: 0.180

Gnomad ASJ AF: 0.0527

Gnomad EAS AF: 0.0903

Gnomad SAS AF: 0.0486

Gnomad FIN AF: 0.193

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.0932

GnomAD2 exomes AF: 0.121 AC: 30302 AN: 251390 AF XY: 0.113

Gnomad AFR exome AF: 0.0217

Gnomad AMR exome AF: 0.273

Gnomad ASJ exome AF: 0.0625

Gnomad EAS exome AF: 0.0974

Gnomad FIN exome AF: 0.185

Gnomad NFE exome AF: 0.105

Gnomad OTH exome AF: 0.107

GnomAD4 exome AF: 0.109 AC: 158619 AN: 1461264 Hom.: 9953 Cov.: 32 AF XY: 0.106 AC XY: 76803 AN XY: 726946

African (AFR) AF: 0.0192 AC: 642 AN: 33460

American (AMR) AF: 0.260 AC: 11646 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0571 AC: 1492 AN: 26132

East Asian (EAS) AF: 0.0836 AC: 3318 AN: 39696

South Asian (SAS) AF: 0.0486 AC: 4194 AN: 86224

European-Finnish (FIN) AF: 0.176 AC: 9422 AN: 53388

Middle Eastern (MID) AF: 0.0634 AC: 340 AN: 5366

European-Non Finnish (NFE) AF: 0.110 AC: 121766 AN: 1111946

Other (OTH) AF: 0.0961 AC: 5799 AN: 60340

GnomAD4 genome AF: 0.0941 AC: 14315 AN: 152202 Hom.: 1007 Cov.: 33 AF XY: 0.0980 AC XY: 7295 AN XY: 74402

African (AFR) AF: 0.0231 AC: 958 AN: 41554

American (AMR) AF: 0.181 AC: 2766 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0527 AC: 183 AN: 3470

East Asian (EAS) AF: 0.0903 AC: 468 AN: 5182

South Asian (SAS) AF: 0.0492 AC: 237 AN: 4814

European-Finnish (FIN) AF: 0.193 AC: 2042 AN: 10576

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.106 AC: 7232 AN: 68002

Other (OTH) AF: 0.0913 AC: 193 AN: 2114

Alfa AF: 0.0989 Hom.: 2929

Bravo AF: 0.0934

TwinsUK AF: 0.115 AC: 428

ALSPAC AF: 0.108 AC: 417

ESP6500AA AF: 0.0245 AC: 108

ESP6500EA AF: 0.0985 AC: 847

ExAC AF: 0.109 AC: 13249

Asia WGS AF: 0.0630 AC: 219 AN: 3478

EpiCase AF: 0.103

EpiControl AF: 0.0992

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	14
DANN	Benign	0.16
DEOGEN2	Benign	0.0028	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0011	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.9	N
PhyloP100		3.4
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	3.1	N
REVEL	Benign	0.10
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0020	B
Vest4		0.049
MPC		0.19
ClinPred		0.0055	T
GERP RS		1.6
Varity_R		0.064
gMVP		0.45
Mutation Taster		=98/2	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: rs1009668; hg19: chr1-226040404; COSMIC: COSV64763304; COSMIC: COSV64763304;