6-44139601-A-G

Variant names:

• chr6-44139601-A-G
• NM_018426.3:c.542A>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018426.3(TMEM63B):​c.542A>G​(p.Asp181Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM63B NM_018426.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.05

Genes affected

TMEM63B (HGNC:17735): (transmembrane protein 63B) Predicted to enable calcium activated cation channel activity; mechanosensitive ion channel activity; and osmolarity-sensing cation channel activity. Predicted to be involved in cation transmembrane transport. Located in actin cytoskeleton and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34339496).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM63B	NM_018426.3	c.542A>G	p.Asp181Gly	missense_variant	Exon 7 of 24	ENST00000323267.11	NP_060896.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM63B	ENST00000323267.11	c.542A>G	p.Asp181Gly	missense_variant	Exon 7 of 24	5	NM_018426.3	ENSP00000327154.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 68

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jan 16, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.542A>G (p.D181G) alteration is located in exon 7 (coding exon 6) of the TMEM63B gene. This alteration results from a A to G substitution at nucleotide position 542, causing the aspartic acid (D) at amino acid position 181 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T;.;T
Eigen	Benign	0.15
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	.;D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.34	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;.;M
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-4.2	D;D;D
REVEL	Benign	0.13
Sift	Benign	0.060	T;T;T
Sift4G	Benign	0.13	T;T;T
Polyphen		0.0090	B;.;B
Vest4		0.48
MutPred		0.38		Loss of stability (P = 0.0537);Loss of stability (P = 0.0537);Loss of stability (P = 0.0537);
MVP		0.21
MPC		1.4
ClinPred		0.97	D
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-44107338;