1-28592578-A-C

Variant names:

• chr1-28592578-A-C
• rs1666338613
• NM_001193532.3:c.67A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001193532.3(RAB42):​c.67A>C​(p.Thr23Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000328 in 1,218,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000019 (0 hom.)
• Consequence: RAB42 NM_001193532.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.54
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40367606).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001193532.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB42	NM_001193532.3	MANE Select	c.67A>C	p.Thr23Pro	missense	Exon 1 of 2	NP_001180461.1	Q8N4Z0-2
	RAB42	NM_001385188.1		c.67A>C	p.Thr23Pro	missense	Exon 1 of 2	NP_001372117.1
	RAB42	NM_152304.3		c.-107+179A>C		intron	N/A	NP_689517.1	Q8N4Z0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAB42	ENST00000465518.3	TSL:2 MANE Select	c.67A>C	p.Thr23Pro	missense	Exon 1 of 2	ENSP00000491546.1	Q8N4Z0-2
	RAB42	ENST00000373826.3	TSL:1	c.-107+179A>C		intron	N/A	ENSP00000362932.3	Q8N4Z0-1
	TAF12	ENST00000688108.1		c.451-2192T>G		intron	N/A	ENSP00000510282.1	A0A8I5KTB6

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151608 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000187 AC: 2 AN: 1067260 Hom.: 0 Cov.: 31 AF XY: 0.00000198 AC XY: 1 AN XY: 503828

African (AFR) AF: 0.00 AC: 0 AN: 22392

American (AMR) AF: 0.00 AC: 0 AN: 7966

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13698

East Asian (EAS) AF: 0.00 AC: 0 AN: 25414

South Asian (SAS) AF: 0.00 AC: 0 AN: 19420

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20944

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2852

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 911902

Other (OTH) AF: 0.0000469 AC: 2 AN: 42672

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151716 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74162

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.000131 AC: 2 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5138

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10434

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67866

Other (OTH) AF: 0.00 AC: 0 AN: 2102

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	29
DANN	Benign	0.72
DEOGEN2	Benign	0.13	T
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.40	T
PhyloP100		4.5
PrimateAI	Pathogenic	0.93	D
GERP RS		3.6
PromoterAI		-0.025	Neutral
Varity_R		0.41
gMVP		0.61
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs1666338613; hg19: chr1-28919090;