ENST00000448430.6:c.1090C>G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000448430.6(DNAAF4):​c.1090C>G​(p.Pro364Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000316 in 1,580,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/17 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: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: DNAAF4 ENST00000448430.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.698
• Publications: 2 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]

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.040132344).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIERCE2	NM_001198784.2	c.19-132G>C		intron_variant	Intron 1 of 1	ENST00000569691.2	NP_001185713.1
DNAAF4	NM_001033560.2	c.1090C>G	p.Pro364Ala	missense_variant	Exon 9 of 9		NP_001028732.1
DNAAF4-CCPG1	NR_037923.1	n.1408+14406C>G		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>C		intron_variant	Intron 1 of 1	1	NM_001198784.2	ENSP00000456337.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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

GnomAD4 exome AF: 0.00000280 AC: 4 AN: 1428522 Hom.: 0 Cov.: 28 AF XY: 0.00000282 AC XY: 2 AN XY: 710242

African (AFR) AF: 0.0000317 AC: 1 AN: 31578

American (AMR) AF: 0.00 AC: 0 AN: 36366

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24010

East Asian (EAS) AF: 0.00 AC: 0 AN: 39544

South Asian (SAS) AF: 0.00 AC: 0 AN: 80134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52868

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5570

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1099542

Other (OTH) AF: 0.0000509 AC: 3 AN: 58910

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74346

African (AFR) AF: 0.0000241 AC: 1 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.012
DANN	Benign	0.33
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0014	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.00057	T
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-0.95	T
PhyloP100		-0.70
PROVEAN	Benign	1.3	N
REVEL	Benign	0.0080
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.094
MutPred		0.30		Gain of helix (P = 0.0128);
MVP		0.099
ClinPred		0.040	T
GERP RS		-0.32
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs199564997; hg19: chr15-55710289;