rs57809907

Variant names:

• chr15-55430684-C-A
• rs57809907
• NM_130810.4:c.1249G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PVS1_Moderate BP6_Very_Strong BA1

The NM_130810.4(DNAAF4):​c.1249G>T​(p.Glu417*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 1,611,952 control chromosomes in the GnomAD database, including 13,397 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (4178 hom., cov: 32)
  • Exomes 𝑓: 0.096 (9219 hom.)
• Consequence: DNAAF4 NM_130810.4 stop_gained
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 0.351

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 -14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0111 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• BP6: Variant 15-55430684-C-A is Benign according to our data. Variant chr15-55430684-C-A is described in ClinVar as [Benign]. Clinvar id is 2136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.415 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAAF4	NM_130810.4	c.1249G>T	p.Glu417*	stop_gained	Exon 10 of 10	ENST00000321149.7	NP_570722.2
DNAAF4	NM_001033559.3	c.*12G>T		3_prime_UTR_variant	Exon 9 of 9		NP_001028731.1
DNAAF4	NM_001033560.2	c.1047+4221G>T		intron_variant	Intron 8 of 8		NP_001028732.1
DNAAF4-CCPG1	NR_037923.1	n.1408+1813G>T		intron_variant	Intron 8 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAAF4	ENST00000321149.7	c.1249G>T	p.Glu417*	stop_gained	Exon 10 of 10	1	NM_130810.4	ENSP00000323275.3

Frequencies

GnomAD3 genomes AF: 0.178 AC: 27025 AN: 151988 Hom.: 4172 Cov.: 32

Gnomad AFR AF: 0.421

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.122

Gnomad EAS AF: 0.0108

Gnomad SAS AF: 0.114

Gnomad FIN AF: 0.0849

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0852

Gnomad OTH AF: 0.148

GnomAD2 exomes AF: 0.104 AC: 26061 AN: 250812 AF XY: 0.102

Gnomad AFR exome AF: 0.426

Gnomad AMR exome AF: 0.0551

Gnomad ASJ exome AF: 0.119

Gnomad EAS exome AF: 0.00805

Gnomad FIN exome AF: 0.0793

Gnomad NFE exome AF: 0.0860

Gnomad OTH exome AF: 0.0962

GnomAD4 exome AF: 0.0964 AC: 140755 AN: 1459846 Hom.: 9219 Cov.: 31 AF XY: 0.0965 AC XY: 70106 AN XY: 726294

Gnomad4 AFR exome AF: 0.438 AC: 14621 AN: 33418

Gnomad4 AMR exome AF: 0.0612 AC: 2730 AN: 44634

Gnomad4 ASJ exome AF: 0.124 AC: 3241 AN: 26070

Gnomad4 EAS exome AF: 0.00551 AC: 218 AN: 39534

Gnomad4 SAS exome AF: 0.127 AC: 10932 AN: 86008

Gnomad4 FIN exome AF: 0.0823 AC: 4378 AN: 53184

Gnomad4 NFE exome AF: 0.0876 AC: 97333 AN: 1111018

Gnomad4 Remaining exome AF: 0.110 AC: 6601 AN: 60280

GnomAD4 genome AF: 0.178 AC: 27065 AN: 152106 Hom.: 4178 Cov.: 32 AF XY: 0.175 AC XY: 13000 AN XY: 74354

Gnomad4 AFR AF: 0.421 AC: 0.420668 AN: 0.420668

Gnomad4 AMR AF: 0.101 AC: 0.101466 AN: 0.101466

Gnomad4 ASJ AF: 0.122 AC: 0.122408 AN: 0.122408

Gnomad4 EAS AF: 0.0108 AC: 0.010815 AN: 0.010815

Gnomad4 SAS AF: 0.114 AC: 0.114363 AN: 0.114363

Gnomad4 FIN AF: 0.0849 AC: 0.0849395 AN: 0.0849395

Gnomad4 NFE AF: 0.0852 AC: 0.0852228 AN: 0.0852228

Gnomad4 OTH AF: 0.147 AC: 0.147448 AN: 0.147448

Alfa AF: 0.112 Hom.: 5065

Bravo AF: 0.188

TwinsUK AF: 0.0890 AC: 330

ALSPAC AF: 0.0825 AC: 318

ESP6500AA AF: 0.416 AC: 1825

ESP6500EA AF: 0.0892 AC: 765

ExAC AF: 0.112 AC: 13636

Asia WGS AF: 0.0840 AC: 291 AN: 3474

EpiCase AF: 0.0916

EpiControl AF: 0.0925

ClinVar

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 17, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 23341075, 12954984, 31213628) -

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency, variant associated with dyslexia -

Primary ciliary dyskinesia 25 Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dyslexia, susceptibility to, 1 Other:1

Sep 30, 2003

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Benign	0.33	N
Vest4		0.38
GERP RS		4.7
Mutation Taster		=177/23	polymorphism (auto)

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: rs57809907; hg19: chr15-55722882; COSMIC: COSV58247741;