12-106608780-C-CTT

Variant names:

• chr12-106608780-C-CTT
• rs55993073
• NM_213594.3:c.44-4_44-3dupTT

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PVS1_Moderate BP6

The NM_213594.3(RFX4):​c.44-4_44-3dupTT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00097 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RFX4 NM_213594.3 splice_acceptor, intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• 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: Uncertain_significance. The variant received 1 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: tcttttttttttttttttAGaga. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• BP6: Variant 12-106608780-C-CTT is Benign according to our data. Variant chr12-106608780-C-CTT is described in ClinVar as Likely_benign. ClinVar VariationId is 3042661.Status of the report is no_assertion_criteria_provided, 0 stars.

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.44-4_44-3dupTT		splice_acceptor intron	N/A	NP_998759.1	Q33E94-1
	RFX4	NM_001206691.2		c.71-4_71-3dupTT		splice_acceptor intron	N/A	NP_001193620.1	Q33E94-2
	LOC100287944	NR_040246.1		n.143-100972_143-100971dupAA		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_44-16insTT		intron	N/A	ENSP00000376585.1	Q33E94-1
	RFX4	ENST00000357881.8	TSL:1	c.71-17_71-16insTT		intron	N/A	ENSP00000350552.4	Q33E94-2
	RFX4	ENST00000536688.5	TSL:1	n.176-17_176-16insTT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 143726 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00280 AC: 343 AN: 122688 AF XY: 0.00285

Gnomad AFR exome AF: 0.00188

Gnomad AMR exome AF: 0.00400

Gnomad ASJ exome AF: 0.00175

Gnomad EAS exome AF: 0.00888

Gnomad FIN exome AF: 0.00178

Gnomad NFE exome AF: 0.00233

Gnomad OTH exome AF: 0.00309

GnomAD4 exome AF: 0.000966 AC: 1231 AN: 1274724 Hom.: 0 Cov.: 0 AF XY: 0.00101 AC XY: 643 AN XY: 634904

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

African (AFR) AF: 0.000762 AC: 21 AN: 27572

American (AMR) AF: 0.00251 AC: 72 AN: 28630

Ashkenazi Jewish (ASJ) AF: 0.00140 AC: 31 AN: 22092

East Asian (EAS) AF: 0.00170 AC: 61 AN: 35926

South Asian (SAS) AF: 0.00272 AC: 192 AN: 70574

European-Finnish (FIN) AF: 0.00118 AC: 48 AN: 40700

Middle Eastern (MID) AF: 0.000592 AC: 3 AN: 5064

European-Non Finnish (NFE) AF: 0.000759 AC: 752 AN: 991060

Other (OTH) AF: 0.000960 AC: 51 AN: 53106

⚠️ 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 Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 143726 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 69746

African (AFR) AF: 0.00 AC: 0 AN: 39266

American (AMR) AF: 0.00 AC: 0 AN: 14388

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4912

South Asian (SAS) AF: 0.00 AC: 0 AN: 4552

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 296

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65502

Other (OTH) AF: 0.00 AC: 0 AN: 1964

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	RFX4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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

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;