3-100555274-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_018004.3(TMEM45A):c.63G>C(p.Trp21Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM45A NM_018004.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.30

Genes affected

TMEM45A (HGNC:25480): (transmembrane protein 45A) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.915

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM45A	NM_018004.3	c.63G>C	p.Trp21Cys	missense_variant	2/6	ENST00000323523.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM45A	ENST00000323523.8	c.63G>C	p.Trp21Cys	missense_variant	2/6	1	NM_018004.3	P1
TMEM45A	ENST00000403410.5	c.111G>C	p.Trp37Cys	missense_variant	4/8	5
TMEM45A	ENST00000449609.1	c.111G>C	p.Trp37Cys	missense_variant	3/5	3
TMEM45A	ENST00000462884.1	n.220G>C		non_coding_transcript_exon_variant	3/4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 18, 2021

The c.63G>C (p.W21C) alteration is located in exon 2 (coding exon 1) of the TMEM45A gene. This alteration results from a G to C substitution at nucleotide position 63, causing the tryptophan (W) at amino acid position 21 to be replaced by a cysteine (C). 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	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D;.;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.77	T;T;T
M_CAP	Benign	0.070	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Pathogenic	3.2	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-12	D;D;D
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;.;B
Vest4		0.59
MutPred		0.73		Loss of MoRF binding (P = 0.0379);.;.;
MVP		0.37
MPC		1.1
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.92
gMVP		0.85

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

Publications

LitVar

Other links and lift over

dbSNP: rs1706192533; hg19: chr3-100274118;