Genetic Variant NM_024587.4:c.827G>T (chr1-44654566-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024587.4(TMEM53):c.827G>T(p.Arg276Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,450,412 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. R276C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

TMEM53
NM_024587.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.16

Publications

0 publications found

Variant links:

Genes affected

TMEM53 (HGNC:26186): (transmembrane protein 53) Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

TMEM53 Gene-Disease associations (from GenCC):

craniotubular dysplasia, Ikegawa type
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
skeletal dysplasia
Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia

TMEM53 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07891473).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024587.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMEM53	NM_024587.4	MANE Select	c.827G>T	p.Arg276Leu	missense	Exon 3 of 3	NP_078863.2
TMEM53	NM_001300747.2		c.737G>T	p.Arg246Leu	missense	Exon 3 of 3	NP_001287676.1	Q5TDE2
TMEM53	NM_001300748.2		c.734G>T	p.Arg245Leu	missense	Exon 3 of 3	NP_001287677.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMEM53	ENST00000372237.8	TSL:1 MANE Select	c.827G>T	p.Arg276Leu	missense	Exon 3 of 3	ENSP00000361311.3	Q6P2H8-1
TMEM53	ENST00000476724.1	TSL:1	n.756G>T		non_coding_transcript_exon	Exon 2 of 2
TMEM53	ENST00000372235.7	TSL:2	c.737G>T	p.Arg246Leu	missense	Exon 3 of 3	ENSP00000361309.3	Q5TDE2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.89e-7

AC:

AN:

1450412

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

718984

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33326

American (AMR)

AF:

0.00

AC:

AN:

44516

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25868

East Asian (EAS)

AF:

0.00

AC:

AN:

39354

South Asian (SAS)

AF:

0.00

AC:

AN:

85830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52962

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

9.07e-7

AC:

AN:

1102986

Other (OTH)

AF:

0.00

AC:

AN:

59822

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.028

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.45

M_CAP

Benign

0.0055

MetaRNN

Benign

0.079

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.20

PhyloP100

1.2

PrimateAI

Benign

0.28

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.058

Sift

Benign

0.040

Sift4G

Benign

0.083

Polyphen

0.20

Vest4

0.13

MutPred

0.41

Loss of disorder (P = 0.0016)

MVP

0.014

MPC

0.66

ClinPred

0.12

GERP RS

-1.1

Varity_R

0.072

gMVP

0.48

Mutation Taster

=96/4

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over