3-100558549-G-T

Position:

• chr3-100558549-G-T

Variant summary

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

The NM_018004.3(TMEM45A):​c.548G>T​(p.Arg183Leu) variant causes a missense change. 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: 4.47

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, 0.903

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM45A	NM_018004.3	c.548G>T	p.Arg183Leu	missense_variant	4/6	ENST00000323523.8	NP_060474.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM45A	ENST00000323523.8	c.548G>T	p.Arg183Leu	missense_variant	4/6	1	NM_018004.3	ENSP00000319009.4
TMEM45A	ENST00000403410.5	c.596G>T	p.Arg199Leu	missense_variant	6/8	5		ENSP00000385089.1
TMEM45A	ENST00000449609.1	c.*22G>T		downstream_gene_variant		3		ENSP00000405597.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Mar 02, 2023

The c.548G>T (p.R183L) alteration is located in exon 4 (coding exon 3) of the TMEM45A gene. This alteration results from a G to T substitution at nucleotide position 548, causing the arginine (R) at amino acid position 183 to be replaced by a leucine (L). 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	Uncertain	0.42
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T;.
Eigen	Benign	-0.054
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.67	T;T
M_CAP	Benign	0.025	T
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Benign	-0.86	T
MutationAssessor	Pathogenic	3.4	M;.
PrimateAI	Benign	0.31	T
PROVEAN	Pathogenic	-5.9	D;D
REVEL	Benign	0.25
Sift	Benign	0.056	T;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		0.64	P;.
Vest4		0.71
MutPred		0.71		Loss of methylation at R183 (P = 0.0552);.;
MVP		0.53
MPC		0.41
ClinPred		0.92	D
GERP RS		3.1
Varity_R		0.28
gMVP		0.87

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-100277393;