11-67464833-C-G

Variant names:

• chr11-67464833-C-G
• rs779599299
• NM_025124.4:c.475G>C

Variant summary

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

The NM_025124.4(TMEM134):​c.475G>C​(p.Val159Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,146 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TMEM134 NM_025124.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.56

Genes affected

TMEM134 (HGNC:26142): (transmembrane protein 134) Located in cytosol and perinuclear region of cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM134	NM_025124.4	c.475G>C	p.Val159Leu	missense_variant	Exon 6 of 7	ENST00000308022.7	NP_079400.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM134	ENST00000308022.7	c.475G>C	p.Val159Leu	missense_variant	Exon 6 of 7	2	NM_025124.4	ENSP00000312615.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000420 AC: 1 AN: 238130 Hom.: 0 AF XY: 0.00000760 AC XY: 1 AN XY: 131620

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 SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458146 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 725300

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

Bravo AF: 0.00000378

ExAC AF: 0.00000833 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.475G>C (p.V159L) alteration is located in exon 6 (coding exon 6) of the TMEM134 gene. This alteration results from a G to C substitution at nucleotide position 475, causing the valine (V) at amino acid position 159 to be replaced by a leucine (L). 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	Uncertain	0.44
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.031	T;.
Eigen	Benign	0.037
Eigen_PC	Benign	0.065
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.51	D;D
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.90	L;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.3	N;N
REVEL	Uncertain	0.48
Sift	Benign	0.074	T;T
Sift4G	Benign	0.29	T;T
Polyphen		1.0	D;B
Vest4		0.69
MutPred		0.57		Loss of sheet (P = 0.0181);.;
MVP		0.22
MPC		0.16
ClinPred		0.33	T
GERP RS		2.7
Varity_R		0.16
gMVP		0.41

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

LitVar

Other links and lift over

dbSNP: rs779599299; hg19: chr11-67232304;