chr12-106687062-G-T

Variant names:

• chr12-106687062-G-T
• rs201207625
• NM_213594.3:c.556G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_213594.3(RFX4):​c.556G>T​(p.Asp186Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RFX4 NM_213594.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.56

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]

ENSG00000257545 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFX4	NM_213594.3	c.556G>T	p.Asp186Tyr	missense_variant	Exon 6 of 18	ENST00000392842.6	NP_998759.1
RFX4	NM_001206691.2	c.583G>T	p.Asp195Tyr	missense_variant	Exon 6 of 18		NP_001193620.1
RFX4	NM_032491.6	c.274G>T	p.Asp92Tyr	missense_variant	Exon 2 of 14		NP_115880.2
LOC100287944	NR_040246.1	n.142+87628C>A		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFX4	ENST00000392842.6	c.556G>T	p.Asp186Tyr	missense_variant	Exon 6 of 18	1	NM_213594.3	ENSP00000376585.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251452 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135902

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS 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: 6.84e-7 AC: 1 AN: 1461820 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 727212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	D;.;.;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Benign	0.067	D
MetaRNN	Uncertain	0.58	D;D;D;D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Benign	1.2	L;.;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-2.3	N;N;D;N
REVEL	Uncertain	0.41
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.060	T;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.84
MutPred		0.30		Loss of disorder (P = 0.0575);.;.;.;
MVP		0.44
MPC		1.4
ClinPred		0.81	D
GERP RS		5.8
Varity_R		0.40
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs201207625; hg19: chr12-107080840; COSMIC: COSV57575475; COSMIC: COSV57575475;