chr12-106601331-C-G

Position:

• chr12-106601331-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000357881.8(RFX4):​c.55C>G​(p.Arg19Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00146 in 1,586,762 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0077 (15 hom., cov: 33)
  • Exomes 𝑓: 0.00081 (14 hom.)
• Consequence: RFX4 ENST00000357881.8 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.56

Genes affected

RFX4 (HGNC:9985): (regulatory factor X4) This gene is a member of the regulatory factor X gene family, which encodes transcription factors that contain a highly-conserved winged helix DNA binding domain. The protein encoded by this gene is structurally related to regulatory factors X1, X2, X3, and X5. It has been shown to interact with itself as well as with regulatory factors X2 and X3, but it does not interact with regulatory factor X1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2011]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028620362).
• BP6: Variant 12-106601331-C-G is Benign according to our data. Variant chr12-106601331-C-G is described in ClinVar as [Benign]. Clinvar id is 713419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00766 (1166/152310) while in subpopulation AFR AF= 0.0265 (1100/41564). AF 95% confidence interval is 0.0252. There are 15 homozygotes in gnomad4. There are 551 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1166 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RFX4	NM_213594.3	c.44-7466C>G		intron_variant		ENST00000392842.6
LOC100287944	NR_040246.1	n.143-93521G>C		intron_variant, non_coding_transcript_variant
RFX4	NM_001206691.2	c.55C>G	p.Arg19Gly	missense_variant	1/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RFX4	ENST00000392842.6	c.44-7466C>G		intron_variant		1	NM_213594.3	P1
	ENST00000551505.4	n.230-101149G>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00765 AC: 1165 AN: 152192 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.0265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00203 AC: 414 AN: 204382 Hom.: 6 AF XY: 0.00148 AC XY: 163 AN XY: 110140

Gnomad AFR exome AF: 0.0288

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000115

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.000807 AC: 1157 AN: 1434452 Hom.: 14 Cov.: 31 AF XY: 0.000720 AC XY: 512 AN XY: 711064

Gnomad4 AFR exome AF: 0.0283

Gnomad4 AMR exome AF: 0.00201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000242

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000310

Gnomad4 OTH exome AF: 0.00174

GnomAD4 genome AF: 0.00766 AC: 1166 AN: 152310 Hom.: 15 Cov.: 33 AF XY: 0.00740 AC XY: 551 AN XY: 74472

Gnomad4 AFR AF: 0.0265

Gnomad4 AMR AF: 0.00346

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000860 Hom.: 0

Bravo AF: 0.00876

ESP6500AA AF: 0.0268 AC: 118

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00218 AC: 263

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 08, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.029
DANN	Benign	0.91
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.43	N
REVEL	Benign	0.034
Sift	Benign	0.53	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.0040	B
Vest4		0.088
MVP		0.15
MPC		0.56
ClinPred		0.0019	T
GERP RS		-5.0
gMVP		0.30

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: rs138167459; hg19: chr12-106995109;