NM_024587.4:c.827G>C

Variant names:

• chr1-44654566-C-G
• rs372108865
• NM_024587.4:c.827G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024587.4(TMEM53):​c.827G>C​(p.Arg276Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 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)
• Consequence: TMEM53 NM_024587.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.16
• Publications: 1 publications found

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

ACMG classification

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=0.102267355).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM53	NM_024587.4	MANE Select	c.827G>C	p.Arg276Pro	missense	Exon 3 of 3	NP_078863.2
	TMEM53	NM_001300747.2		c.737G>C	p.Arg246Pro	missense	Exon 3 of 3	NP_001287676.1	Q5TDE2
	TMEM53	NM_001300748.2		c.734G>C	p.Arg245Pro	missense	Exon 3 of 3	NP_001287677.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM53	ENST00000372237.8	TSL:1 MANE Select	c.827G>C	p.Arg276Pro	missense	Exon 3 of 3	ENSP00000361311.3	Q6P2H8-1
	TMEM53	ENST00000476724.1	TSL:1	n.756G>C		non_coding_transcript_exon	Exon 2 of 2
	TMEM53	ENST00000372235.7	TSL:2	c.737G>C	p.Arg246Pro	missense	Exon 3 of 3	ENSP00000361309.3	Q5TDE2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	19
DANN	Benign	0.86
DEOGEN2	Benign	0.029	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.2
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.11
Sift	Benign	0.031	D
Sift4G	Benign	0.064	T
Polyphen		0.64	P
Vest4		0.14
MutPred		0.40		Loss of MoRF binding (P = 0.0031)
MVP		0.014
MPC		0.93
ClinPred		0.16	T
GERP RS		-1.1
Varity_R		0.21
gMVP		0.74
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs372108865; hg19: chr1-45120238;