rs57809907

chr15-55430684-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PVS1_Moderate BP6_Very_Strong BA1

The NM_130810.4(DNAAF4):c.1249G>T(p.Glu417Ter) 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:5 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:):

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt
DNAAF4	NM_130810.4	c.1249G>T	p.Glu417Ter	stop_gained	10/10	ENST00000321149.7
DNAAF4-CCPG1	NR_037923.1	n.1408+1813G>T		intron_variant, non_coding_transcript_variant
DNAAF4	NM_001033559.3	c.*12G>T		3_prime_UTR_variant	9/9
DNAAF4	NM_001033560.2	c.1047+4221G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF4	ENST00000321149.7	c.1249G>T	p.Glu417Ter	stop_gained	10/10	1	NM_130810.4	P1

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

GnomAD3 exomes AF: 0.104 AC: 26061 AN: 250812 Hom.: 2430 AF XY: 0.102 AC XY: 13830 AN XY: 135566

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 SAS exome AF: 0.126

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

Gnomad4 AMR exome AF: 0.0612

Gnomad4 ASJ exome AF: 0.124

Gnomad4 EAS exome AF: 0.00551

Gnomad4 SAS exome AF: 0.127

Gnomad4 FIN exome AF: 0.0823

Gnomad4 NFE exome AF: 0.0876

Gnomad4 OTH exome AF: 0.110

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

Gnomad4 AMR AF: 0.101

Gnomad4 ASJ AF: 0.122

Gnomad4 EAS AF: 0.0108

Gnomad4 SAS AF: 0.114

Gnomad4 FIN AF: 0.0849

Gnomad4 NFE AF: 0.0852

Gnomad4 OTH AF: 0.147

Alfa AF: 0.103 Hom.: 1862

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:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	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 -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 17, 2018	This variant is associated with the following publications: (PMID: 23341075, 12954984, 31213628) -

Primary ciliary dyskinesia 25 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Dyslexia, susceptibility to, 1 Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Sep 30, 2003

- -

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
MutationTaster	Benign	0.55	P;P;P;P;P
Vest4		0.38
GERP RS		4.7

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;