3-100558501-C-A

Position:

• chr3-100558501-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018004.3(TMEM45A):​c.500C>A​(p.Ala167Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM45A NM_018004.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.162

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM45A	NM_018004.3	c.500C>A	p.Ala167Asp	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.500C>A	p.Ala167Asp	missense_variant	4/6	1	NM_018004.3	ENSP00000319009.4
TMEM45A	ENST00000403410.5	c.548C>A	p.Ala183Asp	missense_variant	6/8	5		ENSP00000385089.1
TMEM45A	ENST00000449609.1	c.548C>A	p.Ala183Asp	missense_variant	5/5	3		ENSP00000405597.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Oct 11, 2024

The c.500C>A (p.A167D) alteration is located in exon 4 (coding exon 3) of the TMEM45A gene. This alteration results from a C to A substitution at nucleotide position 500, causing the alanine (A) at amino acid position 167 to be replaced by an aspartic acid (D). 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	0.69
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.25	T;.;.
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.64	T;T;T
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.64	D;D;D
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.9	M;.;.
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.1	D;D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.019	D;D;D
Sift4G	Uncertain	0.031	D;D;D
Polyphen		0.99	D;.;P
Vest4		0.78
MutPred		0.68		Loss of catalytic residue at A167 (P = 0.0681);.;.;
MVP		0.55
MPC		1.1
ClinPred		0.76	D
GERP RS		2.9
Varity_R		0.23
gMVP		0.82

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: chr3-100277345;