chr15-55430674-G-C

Position:

chr15-55430674-G-C

Variant summary

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

The NM_130810.4(DNAAF4):c.1259C>G(p.Ser420Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0969 in 1,610,990 control chromosomes in the GnomAD database, including 8,196 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.085 ( 585 hom., cov: 32)

Exomes 𝑓: 0.098 ( 7611 hom. )

Consequence

DNAAF4
NM_130810.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.37

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:):

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=0.0015182495).

BP6

Variant 15-55430674-G-C is Benign according to our data. Variant chr15-55430674-G-C is described in ClinVar as [Benign]. Clinvar id is 262314.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.17 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
DNAAF4	NM_130810.4 linkuse as main transcript	c.1259C>G	p.Ser420Cys	missense_variant	10/10	ENST00000321149.7
DNAAF4-CCPG1	NR_037923.1 linkuse as main transcript	n.1408+1823C>G		intron_variant, non_coding_transcript_variant
DNAAF4	NM_001033559.3 linkuse as main transcript	c.*22C>G		3_prime_UTR_variant	9/9
DNAAF4	NM_001033560.2 linkuse as main transcript	c.1047+4231C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF4	ENST00000321149.7 linkuse as main transcript	c.1259C>G	p.Ser420Cys	missense_variant	10/10	1	NM_130810.4	P1	Q8WXU2-1

Frequencies

GnomAD3 genomes

AF:

0.0854

AC:

12978

AN:

152048

Hom.:

581

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0666

Gnomad AMI

AF:

0.115

Gnomad AMR

AF:

0.0726

Gnomad ASJ

AF:

0.0902

Gnomad EAS

AF:

0.179

Gnomad SAS

AF:

0.114

Gnomad FIN

AF:

0.0573

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.0943

Gnomad OTH

AF:

0.0818

GnomAD3 exomes

AF:

0.0914

AC:

22874

AN:

250224

Hom.:

1247

AF XY:

0.0935

AC XY:

12639

AN XY:

135230

show subpopulations

Gnomad AFR exome

AF:

0.0663

Gnomad AMR exome

AF:

0.0550

Gnomad ASJ exome

AF:

0.0944

Gnomad EAS exome

AF:

0.179

Gnomad SAS exome

AF:

0.110

Gnomad FIN exome

AF:

0.0613

Gnomad NFE exome

AF:

0.0924

Gnomad OTH exome

AF:

0.0924

GnomAD4 exome

AF:

0.0981

AC:

143164

AN:

1458824

Hom.:

7611

Cov.:

AF XY:

0.0984

AC XY:

71393

AN XY:

725746

show subpopulations

Gnomad4 AFR exome

AF:

0.0600

Gnomad4 AMR exome

AF:

0.0570

Gnomad4 ASJ exome

AF:

0.0973

Gnomad4 EAS exome

AF:

0.204

Gnomad4 SAS exome

AF:

0.108

Gnomad4 FIN exome

AF:

0.0598

Gnomad4 NFE exome

AF:

0.0982

Gnomad4 OTH exome

AF:

0.101

GnomAD4 genome

AF:

0.0854

AC:

13001

AN:

152166

Hom.:

585

Cov.:

AF XY:

0.0834

AC XY:

6207

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.0670

Gnomad4 AMR

AF:

0.0724

Gnomad4 ASJ

AF:

0.0902

Gnomad4 EAS

AF:

0.179

Gnomad4 SAS

AF:

0.114

Gnomad4 FIN

AF:

0.0573

Gnomad4 NFE

AF:

0.0943

Gnomad4 OTH

AF:

0.0838

Alfa

AF:

0.0895

Hom.:

215

Bravo

AF:

0.0844

TwinsUK

AF:

0.109

AC:

405

ALSPAC

AF:

0.0968

AC:

373

ESP6500AA

AF:

0.0734

AC:

322

ESP6500EA

AF:

0.0942

AC:

808

ExAC

AF:

0.0918

AC:

11141

Asia WGS

AF:

0.148

AC:

512

AN:

3474

EpiCase

AF:

0.0957

EpiControl

AF:

0.101

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

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 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0082

T;T

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.63

T;.

MetaRNN

Benign

0.0015

T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

P;P;P;P;P

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.8

.;N

REVEL

Benign

0.11

Sift

Pathogenic

0.0

.;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.13

MPC

0.32

ClinPred

0.022

GERP RS

3.5

Varity_R

0.17

gMVP

0.37

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