15-55497712-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3BP6_Very_StrongBA1

The NM_130810.4(DNAAF4):c.271G>A(p.Val91Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0606 in 1,599,962 control chromosomes in the GnomAD database, including 3,360 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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 0.046 ( 234 hom., cov: 32)

Exomes 𝑓: 0.062 ( 3126 hom. )

Consequence

DNAAF4
NM_130810.4 missense, splice_region

Scores

Splicing: ADA: 0.9572

Clinical Significance

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

Conservation

PhyloP100: 1.76

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 -15 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_RF.

BP6

Variant 15-55497712-C-T is Benign according to our data. Variant chr15-55497712-C-T is described in ClinVar as [Benign]. Clinvar id is 416509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0666 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAAF4	NM_130810.4 link	c.271G>A	p.Val91Ile	missense_variant, splice_region_variant	Exon 3 of 10	ENST00000321149.7	NP_570722.2	Q8WXU2-1
DNAAF4	NM_001033560.2 link	c.271G>A	p.Val91Ile	missense_variant, splice_region_variant	Exon 3 of 9		NP_001028732.1	Q8WXU2-2A0A0S2Z5Z4
DNAAF4	NM_001033559.3 link	c.271G>A	p.Val91Ile	missense_variant, splice_region_variant	Exon 3 of 9		NP_001028731.1	Q8WXU2-3
DNAAF4-CCPG1	NR_037923.1 link	n.526G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAAF4	ENST00000321149.7 link	c.271G>A	p.Val91Ile	missense_variant, splice_region_variant	Exon 3 of 10	1	NM_130810.4	ENSP00000323275.3		Q8WXU2-1

Frequencies

GnomAD3 genomes

AF:

0.0460

AC:

6998

AN:

152034

Hom.:

235

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0145

Gnomad AMI

AF:

0.204

Gnomad AMR

AF:

0.0379

Gnomad ASJ

AF:

0.0467

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.0367

Gnomad FIN

AF:

0.0508

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0682

Gnomad OTH

AF:

0.0489

GnomAD3 exomes

AF:

0.0472

AC:

11324

AN:

239708

Hom.:

361

AF XY:

0.0496

AC XY:

6431

AN XY:

129712

show subpopulations

Gnomad AFR exome

AF:

0.0114

Gnomad AMR exome

AF:

0.0322

Gnomad ASJ exome

AF:

0.0427

Gnomad EAS exome

AF:

0.000169

Gnomad SAS exome

AF:

0.0425

Gnomad FIN exome

AF:

0.0533

Gnomad NFE exome

AF:

0.0641

Gnomad OTH exome

AF:

0.0564

GnomAD4 exome

AF:

0.0621

AC:

89973

AN:

1447810

Hom.:

3126

Cov.:

AF XY:

0.0618

AC XY:

44503

AN XY:

719800

show subpopulations

Gnomad4 AFR exome

AF:

0.00995

Gnomad4 AMR exome

AF:

0.0327

Gnomad4 ASJ exome

AF:

0.0428

Gnomad4 EAS exome

AF:

0.000303

Gnomad4 SAS exome

AF:

0.0452

Gnomad4 FIN exome

AF:

0.0551

Gnomad4 NFE exome

AF:

0.0693

Gnomad4 OTH exome

AF:

0.0586

GnomAD4 genome

AF:

0.0460

AC:

7000

AN:

152152

Hom.:

234

Cov.:

AF XY:

0.0444

AC XY:

3304

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.0146

Gnomad4 AMR

AF:

0.0378

Gnomad4 ASJ

AF:

0.0467

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.0361

Gnomad4 FIN

AF:

0.0508

Gnomad4 NFE

AF:

0.0683

Gnomad4 OTH

AF:

0.0483

Alfa

AF:

0.0566

Hom.:

579

Bravo

AF:

0.0440

TwinsUK

AF:

0.0655

AC:

243

ALSPAC

AF:

0.0701

AC:

270

ESP6500AA

AF:

0.0137

AC:

ESP6500EA

AF:

0.0700

AC:

601

ExAC

AF:

0.0477

AC:

5792

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.0640

EpiControl

AF:

0.0642

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

- -

Feb 11, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25525159, 19901951) -

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

0.067

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.00078

.;.;T;T

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.080

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.58

T;T;T;.

MetaRNN

Benign

0.0017

T;T;T;T

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.13

N;N;N;N

REVEL

Benign

0.039

Sift

Benign

0.51

T;T;T;T

Sift4G

Benign

0.45

T;T;T;T

Polyphen

0.0050

B;B;B;B

Vest4

0.12

MPC

0.041

ClinPred

0.011

GERP RS

4.7

Varity_R

0.029

gMVP

0.10

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.96

dbscSNV1_RF

Benign

0.58

SpliceAI score (max)

0.62

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.62

Position offset: 3

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