11-67464647-G-T

Variant names:

• chr11-67464647-G-T
• rs995333739
• NM_025124.4:c.555C>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_025124.4(TMEM134):​c.555C>A​(p.Phe185Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000714 in 1,401,290 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 7.1e-7 (0 hom.)
• Consequence: TMEM134 NM_025124.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.89

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.899

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM134	NM_025124.4	c.555C>A	p.Phe185Leu	missense_variant	Exon 7 of 7	ENST00000308022.7	NP_079400.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM134	ENST00000308022.7	c.555C>A	p.Phe185Leu	missense_variant	Exon 7 of 7	2	NM_025124.4	ENSP00000312615.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.14e-7 AC: 1 AN: 1401290 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 691358

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: 9.26e-7

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

Oct 29, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.555C>A (p.F185L) alteration is located in exon 7 (coding exon 7) of the TMEM134 gene. This alteration results from a C to A substitution at nucleotide position 555, causing the phenylalanine (F) at amino acid position 185 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T;.
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Uncertain	2.3	M;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.026	D;D
Polyphen		0.99	D;B
Vest4		0.71
MutPred		0.82		Loss of sheet (P = 0.0817);.;
MVP		0.067
MPC		0.45
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.62
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs995333739; hg19: chr11-67232118;