Genetic Variant TMEM44:p.Glu3Lys (chr3-194633209-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001011655.3(TMEM44):c.7G>A(p.Glu3Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000253 in 1,462,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

TMEM44
NM_001011655.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.46

Variant links:

Genes affected

TMEM44 (HGNC:25120): (transmembrane protein 44) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM44 links:

TMEM44-AS2 (HGNC:41082): (TMEM44 antisense RNA 2)

TMEM44-AS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2034606).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM44	NM_001011655.3 link	c.7G>A	p.Glu3Lys	missense_variant	Exon 1 of 10	ENST00000347147.9	NP_001011655.1	Q2T9K0-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM44	ENST00000347147.9 link	c.7G>A	p.Glu3Lys	missense_variant	Exon 1 of 10	1	NM_001011655.3	ENSP00000333355.6		Q2T9K0-2

Frequencies

GnomAD3 genomes

AF:

0.0000265

AC:

AN:

150792

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000592

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000251

AC:

AN:

1312194

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

646936

show subpopulations

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:

0.0000299

Gnomad4 OTH exome

AF:

0.0000374

GnomAD4 genome

AF:

0.0000265

AC:

AN:

150792

Hom.:

Cov.:

AF XY:

0.0000407

AC XY:

AN XY:

73622

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000592

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 19, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.7G>A (p.E3K) alteration is located in exon 1 (coding exon 1) of the TMEM44 gene. This alteration results from a G to A substitution at nucleotide position 7, causing the glutamic acid (E) at amino acid position 3 to be replaced by a lysine (K). 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

0.32

BayesDel_addAF

Uncertain

0.019

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0032

T;.;.;.

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.14

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.73

T;T;T;T

M_CAP

Pathogenic

0.31

MetaRNN

Benign

0.20

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.97

L;L;L;L

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-1.2

N;N;N;N

REVEL

Benign

0.075

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;T;T

Polyphen

1.0

D;D;D;.

Vest4

0.15

MutPred

0.21

Gain of ubiquitination at E3 (P = 0.0109);Gain of ubiquitination at E3 (P = 0.0109);Gain of ubiquitination at E3 (P = 0.0109);Gain of ubiquitination at E3 (P = 0.0109);

MVP

0.12

MPC

0.074

ClinPred

0.69

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.34

gMVP

0.22

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

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