1-28593830-T-C

Variant names:

• chr1-28593830-T-C
• rs1666373800
• NM_001193532.3:c.370T>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001193532.3(RAB42):​c.370T>C​(p.Phe124Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAB42 NM_001193532.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.79

Genes affected

RAB42 (HGNC:28702): (RAB42, member RAS oncogene family) Predicted to enable GDP binding activity; GTP binding activity; and GTPase activity. Predicted to be involved in Ras protein signal transduction. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

TAF12 (HGNC:11545): (TATA-box binding protein associated factor 12) Control of transcription by RNA polymerase II involves the basal transcription machinery which is a collection of proteins. These proteins with RNA polymerase II, assemble into complexes which are modulated by transactivator proteins that bind to cis-regulatory elements located adjacent to the transcription start site. Some modulators interact directly with the basal complex, whereas others may act as bridging proteins linking transactivators to the basal transcription factors. Some of these associated factors are weakly attached while others are tightly associated with TBP in the TFIID complex. Among the latter are the TAF proteins. Different TAFs are predicted to mediate the function of distinct transcriptional activators for a variety of gene promoters and RNA polymerases. TAF12 interacts directly with TBP as well as with TAF2I. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Sep 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.838

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAB42	NM_001193532.3	c.370T>C	p.Phe124Leu	missense_variant	Exon 2 of 2	ENST00000465518.3	NP_001180461.1
RAB42	NM_152304.3	c.31T>C	p.Phe11Leu	missense_variant	Exon 2 of 2		NP_689517.1
RAB42	XM_047443959.1	c.31T>C	p.Phe11Leu	missense_variant	Exon 2 of 2		XP_047299915.1
RAB42	NM_001385188.1	c.233+1086T>C		intron_variant	Intron 1 of 1		NP_001372117.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAB42	ENST00000465518.3	c.370T>C	p.Phe124Leu	missense_variant	Exon 2 of 2	2	NM_001193532.3	ENSP00000491546.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.370T>C (p.F124L) alteration is located in exon 2 (coding exon 2) of the RAB42 gene. This alteration results from a T to C substitution at nucleotide position 370, causing the phenylalanine (F) at amino acid position 124 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	23
DANN	Uncertain	1.0
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.78	T;T
M_CAP	Uncertain	0.096	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Uncertain	-0.031	T
MutationAssessor	Benign	0.86	L;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-4.9	D;.
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0040	D;.
Sift4G	Benign	0.076	T;.
Vest4		0.46
MutPred		0.52		Gain of disorder (P = 0.1072);.;
MVP		0.76
MPC		0.56
ClinPred		0.98	D
GERP RS		5.6
Varity_R		0.25
gMVP		0.37

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

Publications

LitVar

Other links and lift over

dbSNP: rs1666373800; hg19: chr1-28920342;