12-106608780-CTTTTTTTTTTTT-CTTTTTTTTTTTTT

Variant names:

• chr12-106608780-C-CT
• rs55993073
• NM_213594.3:c.44-3dupT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PVS1_Moderate BS2

The NM_213594.3(RFX4):​c.44-3dupT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00088 (1 hom., cov: 0)
  • Exomes 𝑓: 0.053 (0 hom.)
• Consequence: RFX4 NM_213594.3 splice_acceptor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.526
• Publications: 2 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: Likely_benign. 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.
• BS2: High AC in GnomAd4 at 127 AD gene.

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.44-3dupT		splice_acceptor intron	N/A	NP_998759.1	Q33E94-1
	RFX4	NM_001206691.2		c.71-3dupT		splice_acceptor intron	N/A	NP_001193620.1	Q33E94-2
	LOC100287944	NR_040246.1		n.143-100971dupA		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_44-16insT		intron	N/A	ENSP00000376585.1	Q33E94-1
	RFX4	ENST00000357881.8	TSL:1	c.71-17_71-16insT		intron	N/A	ENSP00000350552.4	Q33E94-2
	RFX4	ENST00000536688.5	TSL:1	n.176-17_176-16insT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000877 AC: 126 AN: 143664 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000417

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00346

Gnomad SAS AF: 0.00154

Gnomad FIN AF: 0.00233

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000871

Gnomad OTH AF: 0.000509

GnomAD2 exomes AF: 0.0401 AC: 4924 AN: 122688 AF XY: 0.0391

Gnomad AFR exome AF: 0.0270

Gnomad AMR exome AF: 0.0512

Gnomad ASJ exome AF: 0.0337

Gnomad EAS exome AF: 0.105

Gnomad FIN exome AF: 0.0249

Gnomad NFE exome AF: 0.0340

Gnomad OTH exome AF: 0.0562

GnomAD4 exome AF: 0.0531 AC: 65339 AN: 1231342 Hom.: 0 Cov.: 0 AF XY: 0.0528 AC XY: 32420 AN XY: 613724

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

African (AFR) AF: 0.0308 AC: 832 AN: 27020

American (AMR) AF: 0.0454 AC: 1276 AN: 28100

Ashkenazi Jewish (ASJ) AF: 0.0365 AC: 789 AN: 21594

East Asian (EAS) AF: 0.0663 AC: 2250 AN: 33922

South Asian (SAS) AF: 0.0656 AC: 4544 AN: 69218

European-Finnish (FIN) AF: 0.0406 AC: 1604 AN: 39530

Middle Eastern (MID) AF: 0.0328 AC: 163 AN: 4966

European-Non Finnish (NFE) AF: 0.0536 AC: 51213 AN: 955674

Other (OTH) AF: 0.0520 AC: 2668 AN: 51318

⚠️ 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 AF: 0.000884 AC: 127 AN: 143722 Hom.: 1 Cov.: 0 AF XY: 0.000874 AC XY: 61 AN XY: 69786

African (AFR) AF: 0.000457 AC: 18 AN: 39356

American (AMR) AF: 0.000486 AC: 7 AN: 14402

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3378

East Asian (EAS) AF: 0.00347 AC: 17 AN: 4900

South Asian (SAS) AF: 0.00154 AC: 7 AN: 4532

European-Finnish (FIN) AF: 0.00233 AC: 20 AN: 8574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 272

European-Non Finnish (NFE) AF: 0.000871 AC: 57 AN: 65452

Other (OTH) AF: 0.000507 AC: 1 AN: 1972

Alfa AF: 0.00 Hom.: 136

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.53
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs55993073; hg19: chr12-107002558;