Variant rs1085307449 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_017799.4(TMEM260):c.1698_1701del(p.Tyr567ThrfsTer27) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. S565S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Consequence

TMEM260
NM_017799.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 6.19

Variant links:

Genes affected

TMEM260 (HGNC:20185): (transmembrane protein 260) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM260 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 14-56633141-GTATC-G is Pathogenic according to our data. Variant chr14-56633141-GTATC-G is described in ClinVar as [Pathogenic]. Clinvar id is 426076.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-56633141-GTATC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM260	NM_017799.4 linkuse as main transcript	c.1698_1701del	p.Tyr567ThrfsTer27	frameshift_variant	13/16	ENST00000261556.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM260	ENST00000261556.11 linkuse as main transcript	c.1698_1701del	p.Tyr567ThrfsTer27	frameshift_variant	13/16	2	NM_017799.4	P1	Q9NX78-1

Frequencies

GnomAD3 genomes

Cov.:

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Structural heart defects and renal anomalies syndrome

Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	Sep 08, 2021	Truncating mutations of TMEM260 with autosomal recessive inheritance have been reported in multiple families and are associated with exhibited complex congenital heart defects, including atrial and ventricular septal defects (ASDs and VSDs). Tyr567Thrfs*27 was published in a case (Ta-Shma et al 2017) and two further cases (Pagnamenta et al (in press)). Functional studies (Ta-Shma et al 2017) showed reduced levels of only the long isoform, suggesting that the mutation induces nonsense-mediated decay. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 08, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing