2-101397553-C-T

Variant names:

• chr2-101397553-C-T
• rs1220406848
• NM_001145664.2:c.1417G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001145664.2(RFX8):​c.1417G>A​(p.Val473Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000289 in 1,385,348 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 Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: RFX8 NM_001145664.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.839
• 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.028932244).
• BP6: Variant 2-101397553-C-T is Benign according to our data. Variant chr2-101397553-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3788593.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1417G>A	p.Val473Met	missense	Exon 12 of 12	NP_001139136.2	Q6ZV50-3
	RFX8	NM_001367508.1		c.904G>A	p.Val302Met	missense	Exon 13 of 13	NP_001354437.1
	RFX8	NM_001367509.1		c.904G>A	p.Val302Met	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.1417G>A	p.Val473Met	missense	Exon 12 of 12	ENSP00000401536.1	Q6ZV50-3
	RFX8	ENST00000646893.2		c.1756G>A	p.Val586Met	missense	Exon 15 of 15	ENSP00000494249.2	Q6ZV50-1
	RFX8	ENST00000646446.1		c.1630G>A	p.Val544Met	missense	Exon 15 of 15	ENSP00000494216.1	A0A2R8Y560

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 150650 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: 0.00000289 AC: 4 AN: 1385348 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 683102

African (AFR) AF: 0.00 AC: 0 AN: 31200

American (AMR) AF: 0.00 AC: 0 AN: 34310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24874

East Asian (EAS) AF: 0.00 AC: 0 AN: 35554

South Asian (SAS) AF: 0.00 AC: 0 AN: 76874

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49136

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5656

European-Non Finnish (NFE) AF: 0.00000280 AC: 3 AN: 1070214

Other (OTH) AF: 0.0000174 AC: 1 AN: 57530

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000659 Hom.: 0

Bravo AF: 0.0000340

ClinVar

ClinVar submissions

Significance: Likely benign

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	0.073
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.29
DANN	Benign	0.13
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0020	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.029	T
MetaSVM	Benign	-0.95	T
PhyloP100		-0.84
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.030
Sift	Benign	0.81	T
Sift4G	Benign	0.39	T
Polyphen		0.0050	B
Vest4		0.051
MVP		0.030
MPC		0.00049
ClinPred		0.018	T
GERP RS		-3.9
gMVP		0.019
Mutation Taster		=98/2	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: rs1220406848; hg19: chr2-102014015;