20-36606026-G-A

Variant names:

• chr20-36606026-G-A
• rs1464308137
• NM_018840.5:c.75G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

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
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:3
• Conservation: PhyloP100: 7.60

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]

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]

ACMG classification

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 rank	MANE	Protein	UniProt
RAB5IF	NM_018840.5	c.75G>A	p.Trp25*	stop_gained	Exon 1 of 4	ENST00000344795.8	NP_061328.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAB5IF	ENST00000344795.8	c.75G>A	p.Trp25*	stop_gained	Exon 1 of 4	1	NM_018840.5	ENSP00000340164.3
TGIF2-RAB5IF	ENST00000558530.1	c.193-1689G>A		intron_variant	Intron 2 of 4	3		ENSP00000454021.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1376112 Hom.: 0 Cov.: 30 AF XY: 0.00000147 AC XY: 1 AN XY: 678256

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.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: no assertion criteria provided

Submissions by phenotype

Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome 2 Pathogenic:1

Feb 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development 1 Pathogenic:1

-

Ege University Pediatric Genetics, Ege University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

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

Jun 01, 2021

Gene Mapping Laboratory, Hacettepe University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

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	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	41
DANN	Uncertain	0.99
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.25	T
MetaRNN	Pathogenic	0.75	D
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

Other links and lift over

dbSNP: rs1464308137; hg19: chr20-35234429;