12-106689354-A-G

Variant names:

• chr12-106689354-A-G
• NM_213594.3:c.659A>G

Variant summary

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

The NM_213594.3(RFX4):​c.659A>G​(p.Asn220Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,554 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: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RFX4 NM_213594.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.91

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.659A>G	p.Asn220Ser	missense_variant	Exon 7 of 18	ENST00000392842.6	NP_998759.1
RFX4	NM_001206691.2	c.686A>G	p.Asn229Ser	missense_variant	Exon 7 of 18		NP_001193620.1
RFX4	NM_032491.6	c.377A>G	p.Asn126Ser	missense_variant	Exon 3 of 14		NP_115880.2
LOC100287944	NR_040246.1	n.142+85336T>C		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFX4	ENST00000392842.6	c.659A>G	p.Asn220Ser	missense_variant	Exon 7 of 18	1	NM_213594.3	ENSP00000376585.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460554 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726760

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;.;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Benign	0.078	D
MetaRNN	Uncertain	0.65	D;D;D;D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Benign	1.2	L;.;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.1	D;D;D;D
REVEL	Uncertain	0.47
Sift	Benign	0.10	T;T;T;T
Sift4G	Benign	0.092	T;T;T;T
Polyphen		0.96	P;D;.;.
Vest4		0.79
MutPred		0.56		Loss of stability (P = 0.0863);.;.;.;
MVP		0.20
MPC		0.59
ClinPred		0.97	D
GERP RS		5.4
Varity_R		0.27
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-107083132; COSMIC: COSV57578653; COSMIC: COSV57578653;