19-42316928-C-T

Variant names:

• chr19-42316928-C-T
• NM_173633.3:c.865C>T

Variant summary

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

The NM_173633.3(TMEM145):​c.865C>T​(p.Leu289Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,536 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TMEM145 NM_173633.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.19

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

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=0.25037372).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM145	NM_173633.3	c.865C>T	p.Leu289Phe	missense_variant	Exon 11 of 15	ENST00000301204.8	NP_775904.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM145	ENST00000301204.8	c.865C>T	p.Leu289Phe	missense_variant	Exon 11 of 15	2	NM_173633.3	ENSP00000301204.2
TMEM145	ENST00000673205.1	c.865C>T	p.Leu289Phe	missense_variant	Exon 11 of 14			ENSP00000499841.1
TMEM145	ENST00000673187.1	c.907C>T	p.Leu303Phe	missense_variant	Exon 11 of 15			ENSP00000500040.1
TMEM145	ENST00000598766.1	c.937C>T	p.Leu313Phe	missense_variant	Exon 11 of 14	5		ENSP00000470827.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461536 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727090

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 11, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.865C>T (p.L289F) alteration is located in exon 11 (coding exon 11) of the TMEM145 gene. This alteration results from a C to T substitution at nucleotide position 865, causing the leucine (L) at amino acid position 289 to be replaced by a phenylalanine (F). 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	0.15
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.046	T;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.4	N;.
REVEL	Benign	0.055
Sift	Benign	0.15	T;.
Sift4G	Uncertain	0.051	T;D
Polyphen		0.40	B;.
Vest4		0.52
MutPred		0.32		Gain of catalytic residue at L289 (P = 0.0888);.;
MVP		0.26
MPC		0.56
ClinPred		0.56	D
GERP RS		4.0
Varity_R		0.14
gMVP		0.33

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: chr19-42821080;