Genetic Variant TMEM94:p.Leu107Phe (chr17-75486336-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_014738.6(TMEM94):c.319C>T(p.Leu107Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,614,082 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

TMEM94
NM_014738.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.27

Variant links:

Genes affected

TMEM94 (HGNC:28983): (transmembrane protein 94) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM94 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
TMEM94	NM_014738.6 link	c.319C>T	p.Leu107Phe	missense_variant	Exon 5 of 32	ENST00000314256.12	NP_055553.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM94	ENST00000314256.12 link	c.319C>T	p.Leu107Phe	missense_variant	Exon 5 of 32	1	NM_014738.6	ENSP00000313885.7		Q12767-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Dec 26, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.319C>T (p.L107F) alteration is located in exon 5 (coding exon 4) of the TMEM94 gene. This alteration results from a C to T substitution at nucleotide position 319, causing the leucine (L) at amino acid position 107 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

0.11

BayesDel_addAF

Uncertain

0.076

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.098

T;T;.;T;.

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.93

D;D;T;D;D

M_CAP

Benign

0.079

MetaRNN

Benign

0.38

T;T;T;T;T

MetaSVM

Uncertain

0.45

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-2.1

.;N;.;.;N

REVEL

Uncertain

0.40

Sift

Uncertain

0.029

.;D;.;.;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

0.98, 0.99

.;D;.;.;D

Vest4

0.40, 0.45

MutPred

0.37

.;.;.;.;Loss of stability (P = 0.1533);

MVP

0.84

MPC

1.2

ClinPred

0.79

GERP RS

5.3

Varity_R

0.17

gMVP

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.18

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over