chr11-129855854-A-G

Position:

• chr11-129855854-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138788.5(TMEM45B):​c.532A>G​(p.Thr178Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM45B NM_138788.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0880

Genes affected

TMEM45B (HGNC:25194): (transmembrane protein 45B) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.121533155).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM45B	NM_138788.5	c.532A>G	p.Thr178Ala	missense_variant	4/6	ENST00000281441.8	NP_620143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM45B	ENST00000281441.8	c.532A>G	p.Thr178Ala	missense_variant	4/6	2	NM_138788.5	ENSP00000281441	P1
TMEM45B	ENST00000524567.1	c.532A>G	p.Thr178Ala	missense_variant	4/6	1		ENSP00000436293	P1
TMEM45B	ENST00000527754.1	n.683A>G		non_coding_transcript_exon_variant	5/6	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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

Aug 15, 2023

The c.532A>G (p.T178A) alteration is located in exon 4 (coding exon 3) of the TMEM45B gene. This alteration results from a A to G substitution at nucleotide position 532, causing the threonine (T) at amino acid position 178 to be replaced by an alanine (A). 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	0.096
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	17
DANN	Benign	0.90
DEOGEN2	Benign	0.020	T;T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.77	.;T
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	0.79	N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.5	N;N
REVEL	Benign	0.12
Sift	Benign	0.33	T;T
Sift4G	Benign	0.26	T;T
Polyphen		0.0080	B;B
Vest4		0.31
MutPred		0.62		Gain of methylation at R177 (P = 0.1128);Gain of methylation at R177 (P = 0.1128);
MVP		0.24
MPC		0.13
ClinPred		0.16	T
GERP RS		4.8
Varity_R		0.12
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs377214268; hg19: chr11-129725749;