15-55430705-G-C

Variant names:

• chr15-55430705-G-C
• rs749119169
• NM_130810.4:c.1228C>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_130810.4(DNAAF4):​c.1228C>G​(p.Arg410Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,612,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R410L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: DNAAF4 NM_130810.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.90
• Publications: 1 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3166207).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAAF4	NM_130810.4	c.1228C>G	p.Arg410Gly	missense_variant	Exon 10 of 10	ENST00000321149.7	NP_570722.2
DNAAF4	NM_001033559.3	c.1122C>G	p.Phe374Leu	missense_variant	Exon 9 of 9		NP_001028731.1
DNAAF4	NM_001033560.2	c.1047+4200C>G		intron_variant	Intron 8 of 8		NP_001028732.1
DNAAF4-CCPG1	NR_037923.1	n.1408+1792C>G		intron_variant	Intron 8 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAAF4	ENST00000321149.7	c.1228C>G	p.Arg410Gly	missense_variant	Exon 10 of 10	1	NM_130810.4	ENSP00000323275.3

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151994 Hom.: 0 Cov.: 32

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460832 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726760

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39538

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53308

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111482

Other (OTH) AF: 0.00 AC: 0 AN: 60330

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151994 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74240

African (AFR) AF: 0.00 AC: 0 AN: 41386

American (AMR) AF: 0.00 AC: 0 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10536

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	27
DANN	Uncertain	1.0
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-1.1	T
PhyloP100		1.9
PROVEAN	Benign	0.23	N
REVEL	Benign	0.044
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.57	P
Vest4		0.48
MutPred		0.57		Loss of helix (P = 0.0304);
MVP		0.66
ClinPred		0.98	D
GERP RS		5.6
Varity_R		0.42
Mutation Taster		=29/71	disease causing

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: rs749119169; hg19: chr15-55722903;