rs61733359

Positions:

• chr15-55497855-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_130810.4(DNAAF4):​c.128A>G​(p.Asn43Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000757 in 1,610,242 control chromosomes in the GnomAD database, including 10 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00040 (4 hom.)
• Consequence: DNAAF4 NM_130810.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.61

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047905147).
• BP6: Variant 15-55497855-T-C is Benign according to our data. Variant chr15-55497855-T-C is described in ClinVar as [Benign]. Clinvar id is 241831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00422 (642/152254) while in subpopulation AFR AF= 0.0145 (601/41540). AF 95% confidence interval is 0.0135. There are 6 homozygotes in gnomad4. There are 300 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAAF4	NM_130810.4	c.128A>G	p.Asn43Ser	missense_variant	3/10	ENST00000321149.7	NP_570722.2
DNAAF4	NM_001033560.2	c.128A>G	p.Asn43Ser	missense_variant	3/9		NP_001028732.1
DNAAF4	NM_001033559.3	c.128A>G	p.Asn43Ser	missense_variant	3/9		NP_001028731.1
DNAAF4-CCPG1	NR_037923.1	n.383A>G		non_coding_transcript_exon_variant	2/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAAF4	ENST00000321149.7	c.128A>G	p.Asn43Ser	missense_variant	3/10	1	NM_130810.4	ENSP00000323275.3

Frequencies

GnomAD3 genomes AF: 0.00414 AC: 630 AN: 152136 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00106 AC: 261 AN: 247346 Hom.: 0 AF XY: 0.000809 AC XY: 108 AN XY: 133550

Gnomad AFR exome AF: 0.0133

Gnomad AMR exome AF: 0.00105

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000549

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000444

Gnomad OTH exome AF: 0.000661

GnomAD4 exome AF: 0.000396 AC: 577 AN: 1457988 Hom.: 4 Cov.: 32 AF XY: 0.000312 AC XY: 226 AN XY: 724952

Gnomad4 AFR exome AF: 0.0130

Gnomad4 AMR exome AF: 0.00107

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000589

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.00116

GnomAD4 genome AF: 0.00422 AC: 642 AN: 152254 Hom.: 6 Cov.: 32 AF XY: 0.00403 AC XY: 300 AN XY: 74456

Gnomad4 AFR AF: 0.0145

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00119 Hom.: 1

Bravo AF: 0.00459

ESP6500AA AF: 0.0135 AC: 59

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00130 AC: 158

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	17
DANN	Benign	0.84
DEOGEN2	Benign	0.0014	.;.;T;T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.47	N
LIST_S2	Uncertain	0.86	D;D;D;.
MetaRNN	Benign	0.0048	T;T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.64	N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.65	T;T;T;T
Sift4G	Benign	0.60	T;T;T;T
Polyphen		0.37	B;B;B;B
Vest4		0.21
MVP		0.44
MPC		0.051
ClinPred		0.014	T
GERP RS		3.6
Varity_R		0.058
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs61733359; hg19: chr15-55790053; COSMIC: COSV100337015;