2-101397687-C-T

Variant names:

• chr2-101397687-C-T
• rs1472421522
• NM_001145664.2:c.1283G>A

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.1283G>A​(p.Ser428Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000286 in 1,398,548 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 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: 0.0000029 (0 hom.)
• Consequence: RFX8 NM_001145664.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.397
• Publications: 0 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=0.070956856).

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.1283G>A	p.Ser428Asn	missense	Exon 12 of 12	NP_001139136.2	Q6ZV50-3
	RFX8	NM_001367508.1		c.770G>A	p.Ser257Asn	missense	Exon 13 of 13	NP_001354437.1
	RFX8	NM_001367509.1		c.770G>A	p.Ser257Asn	missense	Exon 14 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.1283G>A	p.Ser428Asn	missense	Exon 12 of 12	ENSP00000401536.1	Q6ZV50-3
	RFX8	ENST00000646893.2		c.1622G>A	p.Ser541Asn	missense	Exon 15 of 15	ENSP00000494249.2	Q6ZV50-1
	RFX8	ENST00000646446.1		c.1496G>A	p.Ser499Asn	missense	Exon 15 of 15	ENSP00000494216.1	A0A2R8Y560

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000130 AC: 2 AN: 153292 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000822

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: 0.00000286 AC: 4 AN: 1398548 Hom.: 0 Cov.: 30 AF XY: 0.00000290 AC XY: 2 AN XY: 689746

African (AFR) AF: 0.00 AC: 0 AN: 31550

American (AMR) AF: 0.0000845 AC: 3 AN: 35504

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25160

East Asian (EAS) AF: 0.00 AC: 0 AN: 35724

South Asian (SAS) AF: 0.0000127 AC: 1 AN: 78968

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49280

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078694

Other (OTH) AF: 0.00 AC: 0 AN: 57970

GnomAD4 genome Cov.: 33

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	0.098
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	11
DANN	Benign	0.85
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-0.77	T
PhyloP100		0.40
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.094
Sift	Benign	0.055	T
Sift4G	Uncertain	0.0080	D
Polyphen		0.0040	B
Vest4		0.13
MVP		0.030
MPC		0.00054
ClinPred		0.038	T
GERP RS		0.98
gMVP		0.13
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1472421522; hg19: chr2-102014149;