rs116339967

chr15-55439484-T-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS1

The NM_130810.4(DNAAF4):c.881A>T(p.Lys294Met) variant causes a missense change. The variant allele was found at a frequency of 0.00198 in 1,613,674 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (3 hom.)
• Consequence: DNAAF4 NM_130810.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 5.00

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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11037022).
• BP6: Variant 15-55439484-T-A is Benign according to our data. Variant chr15-55439484-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 410960.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}. Variant chr15-55439484-T-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00203 (2965/1461332) while in subpopulation NFE AF= 0.00254 (2828/1111608). AF 95% confidence interval is 0.00247. There are 3 homozygotes in gnomad4_exome. There are 1394 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAAF4	NM_130810.4	c.881A>T	p.Lys294Met	missense_variant	7/10	ENST00000321149.7
DNAAF4-CCPG1	NR_037923.1	n.1136A>T		non_coding_transcript_exon_variant	6/16
DNAAF4	NM_001033560.2	c.881A>T	p.Lys294Met	missense_variant	7/9
DNAAF4	NM_001033559.3	c.881A>T	p.Lys294Met	missense_variant	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF4	ENST00000321149.7	c.881A>T	p.Lys294Met	missense_variant	7/10	1	NM_130810.4	P1

Frequencies

GnomAD3 genomes AF: 0.00154 AC: 234 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00251

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00116 AC: 292 AN: 251382 Hom.: 0 AF XY: 0.00118 AC XY: 160 AN XY: 135892

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00221

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00203 AC: 2965 AN: 1461332 Hom.: 3 Cov.: 30 AF XY: 0.00192 AC XY: 1394 AN XY: 726984

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.000612

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.00254

Gnomad4 OTH exome AF: 0.00157

GnomAD4 genome AF: 0.00154 AC: 234 AN: 152342 Hom.: 0 Cov.: 32 AF XY: 0.00157 AC XY: 117 AN XY: 74490

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00251

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00203 Hom.: 0

Bravo AF: 0.00164

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000684 AC: 3

ESP6500EA AF: 0.00210 AC: 18

ExAC AF: 0.00108 AC: 131

EpiCase AF: 0.00202

EpiControl AF: 0.00190

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 24, 2019	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect -

DNAAF4-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 03, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Uncertain	0.13
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D;D;D;.
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Uncertain	0.47	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-4.9	D;D;D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.81
MVP		0.92
MPC		0.36
ClinPred		0.092	T
GERP RS		4.0
Varity_R		0.53
gMVP		0.79

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: rs116339967; hg19: chr15-55731682;