rs116339967

Variant names:

• chr15-55439484-T-A
• rs116339967
• NM_130810.4:c.881A>T

Your query was ambiguous. Multiple possible variants found:

• chr15-55439484-T-A
• chr15-55439484-T-C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

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:2 B:2
• Conservation: PhyloP100: 5.00
• Publications: 2 publications found

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: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]

ACMG classification

Our verdict: Benign. The variant received -11 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 VariationId is 410960.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 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 GnomAdExome4. There are 1394 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_130810.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF4	NM_130810.4	MANE Select	c.881A>T	p.Lys294Met	missense	Exon 7 of 10	NP_570722.2	Q8WXU2-1
	DNAAF4	NM_001033560.2		c.881A>T	p.Lys294Met	missense	Exon 7 of 9	NP_001028732.1	Q8WXU2-2
	DNAAF4	NM_001033559.3		c.881A>T	p.Lys294Met	missense	Exon 7 of 9	NP_001028731.1	Q8WXU2-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF4	ENST00000321149.7	TSL:1 MANE Select	c.881A>T	p.Lys294Met	missense	Exon 7 of 10	ENSP00000323275.3	Q8WXU2-1
	DNAAF4	ENST00000448430.6	TSL:1	c.881A>T	p.Lys294Met	missense	Exon 6 of 8	ENSP00000403412.2	Q8WXU2-2
	DNAAF4	ENST00000457155.6	TSL:1	c.881A>T	p.Lys294Met	missense	Exon 6 of 8	ENSP00000402640.2	Q8WXU2-3

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

GnomAD2 exomes AF: 0.00116 AC: 292 AN: 251382 AF XY: 0.00118

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 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

African (AFR) AF: 0.000120 AC: 4 AN: 33468

American (AMR) AF: 0.000425 AC: 19 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.000612 AC: 16 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86228

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00254 AC: 2828 AN: 1111608

Other (OTH) AF: 0.00157 AC: 95 AN: 60374

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

African (AFR) AF: 0.000313 AC: 13 AN: 41580

American (AMR) AF: 0.000589 AC: 9 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00251 AC: 171 AN: 68034

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	DNAAF4-related disorder (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.056	T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.11	T
MetaSVM	Uncertain	0.47	D
PhyloP100		5.0
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	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
Mutation Taster		=68/32	polymorphism

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

Other links and lift over

dbSNP: rs116339967; hg19: chr15-55731682;