NM_173633.3:c.301C>T

Variant names:

• chr19-42314640-C-T
• rs770058053
• NM_173633.3:c.301C>T

Variant summary

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

The NM_173633.3(TMEM145):​c.301C>T​(p.Arg101Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,614,036 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: TMEM145 NM_173633.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.49
• 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 2 ACMG points.

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

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.301C>T	p.Arg101Trp	missense	Exon 4 of 15	NP_775904.2	Q8NBT3
	TMEM145	NM_001366910.1		c.301C>T	p.Arg101Trp	missense	Exon 4 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.301C>T	p.Arg101Trp	missense	Exon 4 of 15	ENSP00000301204.2	Q8NBT3
	TMEM145	ENST00000673205.1		c.301C>T	p.Arg101Trp	missense	Exon 4 of 14	ENSP00000499841.1	A0A5F9ZGX1
	TMEM145	ENST00000673187.1		c.301C>T	p.Arg101Trp	missense	Exon 4 of 15	ENSP00000500040.1	A0A5F9ZH48

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251366 AF XY: 0.0000147

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000239 AC: 35 AN: 1461888 Hom.: 0 Cov.: 35 AF XY: 0.0000206 AC XY: 15 AN XY: 727246

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000252 AC: 28 AN: 1112010

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74308

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	0.0084	T
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	0.16
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.44	N
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.061	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.5
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.028	D
Polyphen		1.0	D
Vest4		0.61
MutPred		0.52		Loss of ubiquitination at K96 (P = 0.0386)
MVP		0.32
MPC		0.61
ClinPred		0.92	D
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.69
Mutation Taster		=64/36	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: rs770058053; hg19: chr19-42818792; COSMIC: COSV56623873; COSMIC: COSV56623873;