ENST00000448430.6:c.1048-4104A>G

Variant names:

• chr15-55422237-T-C
• rs12324434
• ENST00000448430.6:c.1048-4104A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000448430.6(DNAAF4):​c.1048-4104A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.4 in 151,738 control chromosomes in the GnomAD database, including 13,406 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.40 (13406 hom., cov: 31)
• Consequence: DNAAF4 ENST00000448430.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.883
• Publications: 13 publications found

Genes affected

DNAAF4 (HGNC:21493): (dynein axonemal assembly factor 4) This gene encodes a tetratricopeptide repeat domain-containing protein. The encoded protein interacts with estrogen receptors and the heat shock proteins, Hsp70 and Hsp90. An homologous protein in rat has been shown to function in neuronal migration in the developing neocortex. A chromosomal translocation involving this gene is associated with a susceptibility to developmental dyslexia. Mutations in this gene are associated with deficits in reading and spelling. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the downstream cell cycle progression 1 (CCPG1) gene. [provided by RefSeq, Mar 2011]

DNAAF4-CCPG1 (HGNC:43019): (DNAAF4-CCPG1 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring dyslexia susceptibility 1 candidate 1 (DYX1C1) and cell cycle progression 1 (CCPG1) genes on chromosome 15. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Mar 2011]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.732 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAAF4	NM_001033560.2	c.1048-4104A>G		intron_variant	Intron 8 of 8		NP_001028732.1
DNAAF4-CCPG1	NR_037923.1	n.1408+10260A>G		intron_variant	Intron 8 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAAF4	ENST00000448430.6	c.1048-4104A>G		intron_variant	Intron 7 of 7	1		ENSP00000403412.2
DNAAF4	ENST00000524160.5	n.*480+10260A>G		intron_variant	Intron 7 of 8	2		ENSP00000428097.1
DNAAF4-CCPG1	ENST00000565113.5	n.1184+10260A>G		intron_variant	Intron 8 of 15	2
DNAAF4-CCPG1	ENST00000568310.1	n.905+17235A>G		intron_variant	Intron 6 of 9	2

Frequencies

GnomAD3 genomes AF: 0.400 AC: 60700 AN: 151620 Hom.: 13395 Cov.: 31

Gnomad AFR AF: 0.250

Gnomad AMI AF: 0.322

Gnomad AMR AF: 0.554

Gnomad ASJ AF: 0.448

Gnomad EAS AF: 0.752

Gnomad SAS AF: 0.535

Gnomad FIN AF: 0.478

Gnomad MID AF: 0.439

Gnomad NFE AF: 0.407

Gnomad OTH AF: 0.426

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.400 AC: 60729 AN: 151738 Hom.: 13406 Cov.: 31 AF XY: 0.411 AC XY: 30432 AN XY: 74130

African (AFR) AF: 0.250 AC: 10334 AN: 41378

American (AMR) AF: 0.555 AC: 8436 AN: 15204

Ashkenazi Jewish (ASJ) AF: 0.448 AC: 1552 AN: 3468

East Asian (EAS) AF: 0.752 AC: 3868 AN: 5146

South Asian (SAS) AF: 0.535 AC: 2572 AN: 4804

European-Finnish (FIN) AF: 0.478 AC: 5024 AN: 10518

Middle Eastern (MID) AF: 0.452 AC: 131 AN: 290

European-Non Finnish (NFE) AF: 0.407 AC: 27616 AN: 67914

Other (OTH) AF: 0.428 AC: 904 AN: 2110

Alfa AF: 0.407 Hom.: 10714

Bravo AF: 0.403

Asia WGS AF: 0.611 AC: 2125 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	7.8
DANN	Benign	0.69
PhyloP100		0.88
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs12324434; hg19: chr15-55714435;