11-87302339-C-T

Variant summary

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

The NM_022918.4(TMEM135):c.595C>T(p.Pro199Ser) 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. 12/21 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: TMEM135 NM_022918.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.73

Genes affected

TMEM135 (HGNC:26167): (transmembrane protein 135) Predicted to be involved in peroxisome organization. Predicted to act upstream of or within response to cold and response to food. Predicted to be located in mitochondrion and peroxisome. [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=0.24789748).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM135	NM_022918.4	c.595C>T	p.Pro199Ser	missense_variant	8/15	ENST00000305494.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM135	ENST00000305494.6	c.595C>T	p.Pro199Ser	missense_variant	8/15	1	NM_022918.4	P1
TMEM135	ENST00000340353.11	c.529C>T	p.Pro177Ser	missense_variant	7/14	1
TMEM135	ENST00000532959.5	c.208C>T	p.Pro70Ser	missense_variant	5/12	2

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

Jun 30, 2023

The c.595C>T (p.P199S) alteration is located in exon 8 (coding exon 8) of the TMEM135 gene. This alteration results from a C to T substitution at nucleotide position 595, causing the proline (P) at amino acid position 199 to be replaced by a serine (S). 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	0.11
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	20
Dann	Uncertain	0.99
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.25	T;T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.073
Sift	Benign	0.23	T;T;T
Sift4G	Benign	0.21	T;T;T
Polyphen		0.67	P;.;P
Vest4		0.49
MutPred		0.33		.;.;Gain of phosphorylation at P199 (P = 0.0478);
MVP		0.043
MPC		0.38
ClinPred		0.81	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.50

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: chr11-87013381;