11-87318225-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_022918.4(TMEM135):c.1166G>T(p.Cys389Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TMEM135 NM_022918.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.54

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.76

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM135	NM_022918.4	c.1166G>T	p.Cys389Phe	missense_variant	13/15	ENST00000305494.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM135	ENST00000305494.6	c.1166G>T	p.Cys389Phe	missense_variant	13/15	1	NM_022918.4	P1
TMEM135	ENST00000340353.11	c.1100G>T	p.Cys367Phe	missense_variant	12/14	1
TMEM135	ENST00000531643.1	n.91G>T		non_coding_transcript_exon_variant	1/3	1
TMEM135	ENST00000532959.5	c.779G>T	p.Cys260Phe	missense_variant	10/12	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1458316 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725628

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: 0.00

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2023

The c.1166G>T (p.C389F) alteration is located in exon 13 (coding exon 13) of the TMEM135 gene. This alteration results from a G to T substitution at nucleotide position 1166, causing the cysteine (C) at amino acid position 389 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	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
Cadd	Pathogenic	31
Dann	Uncertain	0.99
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Pathogenic	0.76	D;D;D
MetaSVM	Benign	-0.76	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.8	N;N;N
REVEL	Uncertain	0.42
Sift	Benign	0.077	T;T;T
Sift4G	Benign	0.15	T;T;T
Polyphen		0.95	P;.;D
Vest4		0.86
MutPred		0.47		.;.;Gain of glycosylation at T386 (P = 0.2637);
MVP		0.61
MPC		1.1
ClinPred		0.92	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.93

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: chr11-87029267;