rs16976354

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_130810.4(DNAAF4):c.114C>A(p.Asn38Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,613,942 control chromosomes in the GnomAD database, including 1,552 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.055 ( 786 hom., cov: 32)

Exomes 𝑓: 0.0055 ( 766 hom. )

Consequence

DNAAF4
NM_130810.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.0290

Variant links:

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 links:

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]

DNAAF4-CCPG1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0011978745).

BP6

Variant 15-55498216-G-T is Benign according to our data. Variant chr15-55498216-G-T is described in ClinVar as [Benign]. Clinvar id is 416510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.19 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAAF4	NM_130810.4 link	c.114C>A	p.Asn38Lys	missense_variant	Exon 2 of 10	ENST00000321149.7	NP_570722.2	Q8WXU2-1
DNAAF4	NM_001033560.2 link	c.114C>A	p.Asn38Lys	missense_variant	Exon 2 of 9		NP_001028732.1	Q8WXU2-2A0A0S2Z5Z4
DNAAF4	NM_001033559.3 link	c.114C>A	p.Asn38Lys	missense_variant	Exon 2 of 9		NP_001028731.1	Q8WXU2-3
DNAAF4-CCPG1	NR_037923.1 link	n.369C>A		non_coding_transcript_exon_variant	Exon 1 of 16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAAF4	ENST00000321149.7 link	c.114C>A	p.Asn38Lys	missense_variant	Exon 2 of 10	1	NM_130810.4	ENSP00000323275.3		Q8WXU2-1

Frequencies

GnomAD3 genomes

AF:

0.0548

AC:

8345

AN:

152198

Hom.:

784

Cov.:

show subpopulations

Gnomad AFR

AF:

0.194

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0139

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.0363

GnomAD3 exomes

AF:

0.0139

AC:

3492

AN:

250676

Hom.:

321

AF XY:

0.0100

AC XY:

1357

AN XY:

135602

show subpopulations

Gnomad AFR exome

AF:

0.197

Gnomad AMR exome

AF:

0.00685

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000164

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000229

Gnomad OTH exome

AF:

0.00573

GnomAD4 exome

AF:

0.00548

AC:

8008

AN:

1461626

Hom.:

766

Cov.:

AF XY:

0.00465

AC XY:

3379

AN XY:

727112

show subpopulations

Gnomad4 AFR exome

AF:

0.204

Gnomad4 AMR exome

AF:

0.00790

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000278

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000107

Gnomad4 OTH exome

AF:

0.0109

GnomAD4 genome

AF:

0.0549

AC:

8358

AN:

152316

Hom.:

786

Cov.:

AF XY:

0.0532

AC XY:

3961

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.194

Gnomad4 AMR

AF:

0.0140

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.0360

Alfa

AF:

0.0125

Hom.:

263

Bravo

AF:

0.0627

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.194

AC:

849

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0176

AC:

2132

Asia WGS

AF:

0.00837

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000297

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Mar 26, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.75

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.0019

.;.;T;T

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.070

LIST_S2

Uncertain

0.86

D;D;D;.

MetaRNN

Benign

0.0012

T;T;T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.13

N;N;N;N

REVEL

Benign

0.11

Sift

Benign

0.30

T;T;T;T

Sift4G

Benign

0.58

T;T;T;T

Polyphen

0.82

P;B;B;B

Vest4

0.23

MutPred

0.20

Gain of ubiquitination at N38 (P = 0.0211);Gain of ubiquitination at N38 (P = 0.0211);Gain of ubiquitination at N38 (P = 0.0211);Gain of ubiquitination at N38 (P = 0.0211);

MPC

0.075

ClinPred

0.0020

GERP RS

-1.6

Varity_R

0.13

gMVP

0.17

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over