chr19-42315217-C-A

Variant names:

• chr19-42315217-C-A
• rs202212359
• NM_173633.3:c.535C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_173633.3(TMEM145):​c.535C>A​(p.Leu179Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,455,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L179F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TMEM145 NM_173633.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.68
• Publications: 0 publications found

Genes affected

TMEM145 (HGNC:26912): (transmembrane protein 145) Predicted to be involved in G protein-coupled receptor signaling pathway and response to pheromone. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21481359).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173633.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM145	NM_173633.3	MANE Select	c.535C>A	p.Leu179Ile	missense	Exon 7 of 15	NP_775904.2	Q8NBT3
	TMEM145	NM_001366910.1		c.577C>A	p.Leu193Ile	missense	Exon 7 of 15	NP_001353839.1	A0A5F9ZH48

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM145	ENST00000301204.8	TSL:2 MANE Select	c.535C>A	p.Leu179Ile	missense	Exon 7 of 15	ENSP00000301204.2	Q8NBT3
	TMEM145	ENST00000673205.1		c.535C>A	p.Leu179Ile	missense	Exon 7 of 14	ENSP00000499841.1	A0A5F9ZGX1
	TMEM145	ENST00000673187.1		c.577C>A	p.Leu193Ile	missense	Exon 7 of 15	ENSP00000500040.1	A0A5F9ZH48

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 247292 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455588 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 723144

African (AFR) AF: 0.00 AC: 0 AN: 33304

American (AMR) AF: 0.00 AC: 0 AN: 44482

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25640

East Asian (EAS) AF: 0.00 AC: 0 AN: 39602

South Asian (SAS) AF: 0.00 AC: 0 AN: 85628

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53222

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107870

Other (OTH) AF: 0.00 AC: 0 AN: 60102

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.019	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.41	N
PhyloP100		4.7
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.14
Sift	Benign	0.47	T
Sift4G	Benign	0.67	T
Polyphen		0.0010	B
Vest4		0.43
MutPred		0.63		Loss of catalytic residue at L179 (P = 0.0047)
MVP		0.21
MPC		0.52
ClinPred		0.37	T
GERP RS		4.0
Varity_R		0.15
gMVP		0.24
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs202212359; hg19: chr19-42819369;