Variant 20-36606026-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

The NM_018840.5(RAB5IF):c.75G>A(p.Trp25*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,376,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

RAB5IF
NM_018840.5 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic no assertion criteria provided P:3

Conservation

PhyloP100: 7.60

Variant links:

Genes affected

RAB5IF (HGNC:15870): (RAB5 interacting factor) Involved in mitochondrial respirasome assembly. Located in mitochondrial respirasome. [provided by Alliance of Genome Resources, Apr 2022]

RAB5IF links:

TGIF2-RAB5IF (HGNC:44664): (TGIF2-RAB5IF readthrough) This locus represents naturally occurring read-through transcription between the neighboring TGIF2 (TGFB-induced factor homeobox 2) and C20orf24 (chromosome 20 open reading frame 24) genes. The read-through transcript encodes a fusion protein that shares sequence identity with each individual gene product. [provided by RefSeq, Dec 2010]

TGIF2-RAB5IF links:

RAB5IF (HGNC:):

RAB5IF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 20-36606026-G-A is Pathogenic according to our data. Variant chr20-36606026-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 996015.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAB5IF	NM_018840.5 linkuse as main transcript	c.75G>A	p.Trp25*	stop_gained	1/4	ENST00000344795.8	NP_061328.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAB5IF	ENST00000344795.8 linkuse as main transcript	c.75G>A	p.Trp25*	stop_gained	1/4	1	NM_018840.5	ENSP00000340164.3		Q9BUV8-2
TGIF2-RAB5IF	ENST00000558530.1 linkuse as main transcript	c.193-1689G>A		intron_variant		3		ENSP00000454021.1		A0A0A6YYL0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000145

AC:

AN:

1376112

Hom.:

Cov.:

AF XY:

0.00000147

AC XY:

AN XY:

678256

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:

9.38e-7

Gnomad4 OTH exome

AF:

0.0000176

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development 1

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Ege University Pediatric Genetics, Ege University

The c.75G>A variant has not been reported in public databases (GnomAD) to date, and results in a premature termination codon at 25th position of C20orf24 mRNA, a highly conserved amino acid during evolution. -

Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome 2

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2014

- -

Hypertelorism;C0025990:Micrognathia;C0036439:Scoliosis;C0265695:Rib fusion;C1398522:Bilateral cleft lip and palate;C1853241:Flat face;C2243051:Macrocephaly;C3714756:Intellectual disability;C4021789:Abnormality of the vertebral column;C4721788:Bifid ribs

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Gene Mapping Laboratory, Hacettepe University

Jun 01, 2021

The p.Trp25Ter variant has been reported in one Turkish family of consanguineous parents, was absent in large population studies such as gnomAD. The absence of RAB5IF protein has been confirmed in primary skin fibroblasts from the affected individual. This is accompanied by loss of TMCO1 protein in the fibroblasts, which leads to CFSMR (MIM 213980) syndrome, and external introduction of RAB5IF rescues TMCO1 protein levels in fibroblasts. In summary, predicted loss-of-function mutation in homozygosity and strong functional evidence suggest that this variant is pathogenic, leading to CFSMR. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.61

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.25

MetaRNN

Pathogenic

0.75

GERP RS

5.4

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.29

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.29

Position offset: 1

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

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