2-101402682-C-A

Variant names:

• chr2-101402682-C-A
• rs746392837
• NM_001145664.2:c.999G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001145664.2(RFX8):​c.999G>T​(p.Glu333Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000214 in 1,402,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RFX8 NM_001145664.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.25
• Publications: 1 publications found

Genes affected

RFX8 (HGNC:37253): (regulatory factor X8) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. Predicted to be part of chromatin. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13606438).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145664.2. 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
	RFX8	NM_001145664.2	MANE Select	c.999G>T	p.Glu333Asp	missense	Exon 11 of 12	NP_001139136.2	Q6ZV50-3
	RFX8	NM_001367508.1		c.486G>T	p.Glu162Asp	missense	Exon 12 of 13	NP_001354437.1
	RFX8	NM_001367509.1		c.486G>T	p.Glu162Asp	missense	Exon 13 of 14	NP_001354438.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFX8	ENST00000428343.6	TSL:2 MANE Select	c.999G>T	p.Glu333Asp	missense	Exon 11 of 12	ENSP00000401536.1	Q6ZV50-3
	RFX8	ENST00000646893.2		c.1338G>T	p.Glu446Asp	missense	Exon 14 of 15	ENSP00000494249.2	Q6ZV50-1
	RFX8	ENST00000646446.1		c.1212G>T	p.Glu404Asp	missense	Exon 14 of 15	ENSP00000494216.1	A0A2R8Y560

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 163496 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000214 AC: 3 AN: 1402814 Hom.: 0 Cov.: 33 AF XY: 0.00000289 AC XY: 2 AN XY: 692086

African (AFR) AF: 0.00 AC: 0 AN: 31790

American (AMR) AF: 0.00 AC: 0 AN: 36002

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25214

East Asian (EAS) AF: 0.00 AC: 0 AN: 36162

South Asian (SAS) AF: 0.00 AC: 0 AN: 79370

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49750

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 0.00000278 AC: 3 AN: 1080510

Other (OTH) AF: 0.00 AC: 0 AN: 58312

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000957 AC: 1

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	Benign	0.12
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	3.9
DANN	Uncertain	0.98
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.65	T
PhyloP100		-1.3
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.13
Sift	Benign	0.17	T
Sift4G	Benign	0.14	T
Polyphen		0.96	D
Vest4		0.16
MVP		0.014
MPC		0.00055
ClinPred		0.83	D
GERP RS		-3.0
gMVP		0.077
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs746392837; hg19: chr2-102019144;