ENST00000448430.6:c.1090C>A

Variant names:

• chr15-55418091-G-T
• rs199564997
• ENST00000448430.6:c.1090C>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000448430.6(DNAAF4):​c.1090C>A​(p.Pro364Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P364S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DNAAF4 ENST00000448430.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.698

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]

PIERCE2 (HGNC:44654): (piercer of microtubule wall 2)

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.057718337).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIERCE2	NM_001198784.2	c.19-132G>T		intron_variant	Intron 1 of 1	ENST00000569691.2	NP_001185713.1
DNAAF4	NM_001033560.2	c.1090C>A	p.Pro364Thr	missense_variant	Exon 9 of 9		NP_001028732.1
DNAAF4-CCPG1	NR_037923.1	n.1408+14406C>A		intron_variant	Intron 8 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIERCE2	ENST00000569691.2	c.19-132G>T		intron_variant	Intron 1 of 1	1	NM_001198784.2	ENSP00000456337.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1428522 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 710242

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: 0.00

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
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.2
DANN	Benign	0.32
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.00057	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.00052	T
MetaRNN	Benign	0.058	T
MetaSVM	Benign	-0.97	T
PROVEAN	Benign	0.15	N
REVEL	Benign	0.022
Sift	Benign	0.23	T
Sift4G	Benign	0.60	T
Polyphen		0.0010	B
Vest4		0.099
MutPred		0.27		Gain of helix (P = 0.0128);
MVP		0.13
ClinPred		0.093	T
GERP RS		-0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs199564997; hg19: chr15-55710289;