15-55439557-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_130810.4(DNAAF4):c.808C>G(p.Arg270Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,648 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DNAAF4 NM_130810.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.70

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAAF4	NM_130810.4	c.808C>G	p.Arg270Gly	missense_variant	7/10	ENST00000321149.7
DNAAF4-CCPG1	NR_037923.1	n.1063C>G		non_coding_transcript_exon_variant	6/16
DNAAF4	NM_001033560.2	c.808C>G	p.Arg270Gly	missense_variant	7/9
DNAAF4	NM_001033559.3	c.808C>G	p.Arg270Gly	missense_variant	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF4	ENST00000321149.7	c.808C>G	p.Arg270Gly	missense_variant	7/10	1	NM_130810.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461648 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727146

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	0.0035	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.92	D;D;D;.
M_CAP	Benign	0.044	D
MetaRNN	Uncertain	0.69	D;D;D;D
MetaSVM	Benign	-0.55	T
MutationTaster	Benign	0.97	D;D;D;D;D
PrimateAI	Benign	0.33	T
PROVEAN	Pathogenic	-5.7	D;D;D;D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0040	D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		0.90	P;P;D;D
Vest4		0.61
MutPred		0.46		Loss of stability (P = 0.0466);Loss of stability (P = 0.0466);Loss of stability (P = 0.0466);Loss of stability (P = 0.0466);
MVP		0.82
MPC		0.25
ClinPred		0.99	D
GERP RS		2.0
Varity_R		0.56
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397515621; hg19: chr15-55731755;