12-106608780-CTTTTTTTTTTTT-CTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTCTTTTTTTTTTTTT

Variant names:

• chr12-106608780-C-CTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTCT
• rs55993073
• NM_213594.3:c.44-3_44-2insTTTTTTTTTTTTTTTTTTTTTTTTTCTTTTTTTTTTTTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_213594.3(RFX4):​c.44-3_44-2insTTTTTTTTTTTTTTTTTTTTTTTTTCTTTTTTTTTTTTTTT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 7.8e-7 (0 hom.)
• Consequence: RFX4 NM_213594.3 splice_acceptor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.526
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.039402176 fraction of the gene. Cryptic splice site detected, with MaxEntScore 11, offset of 0 (no position change), new splice context is: ttctttttttttttttttAGaga. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_213594.3. 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
	RFX4	NM_213594.3	MANE Select	c.44-3_44-2insTTTTTTTTTTTTTTTTTTTTTTTTTCTTTTTTTTTTTTTTT		splice_acceptor intron	N/A	NP_998759.1	Q33E94-1
	RFX4	NM_001206691.2		c.71-3_71-2insTTTTTTTTTTTTTTTTTTTTTTTTTCTTTTTTTTTTTTTTT		splice_acceptor intron	N/A	NP_001193620.1	Q33E94-2
	LOC100287944	NR_040246.1		n.143-100971_143-100970insAGAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFX4	ENST00000392842.6	TSL:1 MANE Select	c.44-17_44-16insTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTCT		intron	N/A	ENSP00000376585.1	Q33E94-1
	RFX4	ENST00000357881.8	TSL:1	c.71-17_71-16insTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTCT		intron	N/A	ENSP00000350552.4	Q33E94-2
	RFX4	ENST00000536688.5	TSL:1	n.176-17_176-16insTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTCT		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 7.82e-7 AC: 1 AN: 1278178 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 636674

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 27610

American (AMR) AF: 0.00 AC: 0 AN: 28692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22136

East Asian (EAS) AF: 0.00 AC: 0 AN: 36020

South Asian (SAS) AF: 0.00 AC: 0 AN: 70876

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40814

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5068

European-Non Finnish (NFE) AF: 0.00000101 AC: 1 AN: 993716

Other (OTH) AF: 0.00 AC: 0 AN: 53246

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.53

Splicing

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

Other links and lift over

dbSNP: rs55993073; hg19: chr12-107002558;