Genetic Variant TMEM94:p.Arg20Gly (chr17-75485461-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_014738.6(TMEM94):c.58C>G(p.Arg20Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R20W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TMEM94
NM_014738.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.369

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

intellectual developmental disorder with cardiac defects and dysmorphic facies
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, PanelApp Australia, Orphanet, ClinGen, Ambry Genetics

TMEM94 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.057378024).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014738.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TMEM94	NM_014738.6	MANE Select	c.58C>G	p.Arg20Gly	missense	Exon 3 of 32	NP_055553.3
TMEM94	NM_001438842.1		c.58C>G	p.Arg20Gly	missense	Exon 3 of 32	NP_001425771.1
TMEM94	NM_001438843.1		c.88C>G	p.Arg30Gly	missense	Exon 2 of 31	NP_001425772.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMEM94	ENST00000314256.12	TSL:1 MANE Select	c.58C>G	p.Arg20Gly	missense	Exon 3 of 32	ENSP00000313885.7	Q12767-1
TMEM94	ENST00000956011.1		c.58C>G	p.Arg20Gly	missense	Exon 3 of 32	ENSP00000626070.1
TMEM94	ENST00000861539.1		c.58C>G	p.Arg20Gly	missense	Exon 3 of 32	ENSP00000531598.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461788

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727208

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111942

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

0.10

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.069

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.79

M_CAP

Benign

0.0073

MetaRNN

Benign

0.057

MetaSVM

Benign

-1.0

PhyloP100

-0.37

PrimateAI

Benign

0.22

PROVEAN

Benign

-1.6

REVEL

Benign

0.13

Sift

Benign

0.35

Sift4G

Benign

0.43

Polyphen

0.0

Vest4

0.22

MutPred

0.29

Loss of stability (P = 0.0156)

MVP

0.13

MPC

0.50

ClinPred

0.059

GERP RS

-5.0

Varity_R

0.041

gMVP

0.23

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over