rs77641439

chr15-55430674-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.37

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 -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	UniProt
DNAAF4	NM_130810.4	c.1259C>G	p.Ser420Cys	missense_variant	10/10	ENST00000321149.7
DNAAF4-CCPG1	NR_037923.1	n.1408+1823C>G		intron_variant, non_coding_transcript_variant
DNAAF4	NM_001033559.3	c.*22C>G		3_prime_UTR_variant	9/9
DNAAF4	NM_001033560.2	c.1047+4231C>G		intron_variant

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0854 AC: 12978 AN: 152048 Hom.: 581 Cov.: 32

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

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.: 31 AF XY: 0.0984 AC XY: 71393 AN XY: 725746

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.: 32 AF XY: 0.0834 AC XY: 6207 AN XY: 74394

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:4

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 -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0082	T;T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.63	T;.
MetaRNN	Benign	0.0015	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.48	T
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.13
MPC		0.32
ClinPred		0.022	T
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

Other links and lift over

dbSNP: rs77641439; hg19: chr15-55722872; COSMIC: COSV58247414;