1-44654677-C-CGGCGTGCCA

Position:

• chr1-44654677-C-CGGCGTGCCA

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The NM_024587.4(TMEM53):​c.715_716insTGGCACGCC​(p.Leu236_Arg238dup) variant causes a inframe insertion change. The variant allele was found at a frequency of 0.00000684 in 1,461,826 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: TMEM53 NM_024587.4 inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.85

Genes affected

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

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_024587.4.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM53	NM_024587.4	c.715_716insTGGCACGCC	p.Leu236_Arg238dup	inframe_insertion	3/3	ENST00000372237.8	NP_078863.2
TMEM53	NM_001300746.2	c.496_497insTGGCACGCC	p.Leu163_Arg165dup	inframe_insertion	2/2		NP_001287675.1
TMEM53	NM_001300747.2	c.625_626insTGGCACGCC	p.Leu206_Arg208dup	inframe_insertion	3/3		NP_001287676.1
TMEM53	NM_001300748.2	c.622_623insTGGCACGCC	p.Leu205_Arg207dup	inframe_insertion	3/3		NP_001287677.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM53	ENST00000372237.8	c.715_716insTGGCACGCC	p.Leu236_Arg238dup	inframe_insertion	3/3	1	NM_024587.4	ENSP00000361311	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251382 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135882

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461826 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727216

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: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Craniotubular dysplasia, Ikegawa type Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital

Jul 10, 2023

The novel homozygous variant c.707_715dup (p.Leu236_Arg238dup) has been identified in a proband with abnormal facial shape, abnormal vertebral morphology, abnormal visual electrophysiology, abnormality of limb bone morphology, acetabular dysplasia, brachydactyly, brain imaging abnormality, C1-C2 vertebral abnormality, calvarial hyperostosis, contractures of the joints of upper limbs, genu varum, optic atrophy, small hand, short foot, short humerus, short metacarpal, short metatarsal, short stature, microcephaly and scoliosis. This has been found in 0.0004% in gnomAD (aggregated) database (PM2_moderate). Protein length changes due to the deletion (PM4_moderate). -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1557489429; hg19: chr1-45120349;