15-55498112-G-T

Variant names:

• chr15-55498112-G-T
• rs3743204
• NM_130810.4:c.123+95C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_130810.4(DNAAF4):​c.123+95C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.232 in 1,581,588 control chromosomes in the GnomAD database, including 50,845 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (11492 hom., cov: 32)
  • Exomes 𝑓: 0.22 (39353 hom.)
• Consequence: DNAAF4 NM_130810.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.802
• Publications: 33 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 15-55498112-G-T is Benign according to our data. Variant chr15-55498112-G-T is described in ClinVar as [Benign]. Clinvar id is 1250366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.651 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAAF4	NM_130810.4	c.123+95C>A		intron_variant	Intron 2 of 9	ENST00000321149.7	NP_570722.2
DNAAF4	NM_001033560.2	c.123+95C>A		intron_variant	Intron 2 of 8		NP_001028732.1
DNAAF4	NM_001033559.3	c.123+95C>A		intron_variant	Intron 2 of 8		NP_001028731.1
DNAAF4-CCPG1	NR_037923.1	n.378+95C>A		intron_variant	Intron 1 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAAF4	ENST00000321149.7	c.123+95C>A		intron_variant	Intron 2 of 9	1	NM_130810.4	ENSP00000323275.3

Frequencies

GnomAD3 genomes AF: 0.329 AC: 50042 AN: 151952 Hom.: 11452 Cov.: 32

Gnomad AFR AF: 0.657

Gnomad AMI AF: 0.278

Gnomad AMR AF: 0.204

Gnomad ASJ AF: 0.224

Gnomad EAS AF: 0.189

Gnomad SAS AF: 0.286

Gnomad FIN AF: 0.172

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.204

Gnomad OTH AF: 0.290

GnomAD4 exome AF: 0.222 AC: 316861 AN: 1429518 Hom.: 39353 AF XY: 0.223 AC XY: 158522 AN XY: 711054

African (AFR) AF: 0.671 AC: 21060 AN: 31388

American (AMR) AF: 0.150 AC: 5224 AN: 34814

Ashkenazi Jewish (ASJ) AF: 0.231 AC: 5743 AN: 24900

East Asian (EAS) AF: 0.213 AC: 8378 AN: 39376

South Asian (SAS) AF: 0.291 AC: 23468 AN: 80780

European-Finnish (FIN) AF: 0.173 AC: 9137 AN: 52882

Middle Eastern (MID) AF: 0.254 AC: 1442 AN: 5680

European-Non Finnish (NFE) AF: 0.207 AC: 227962 AN: 1100574

Other (OTH) AF: 0.244 AC: 14447 AN: 59124

GnomAD4 genome AF: 0.330 AC: 50133 AN: 152070 Hom.: 11492 Cov.: 32 AF XY: 0.324 AC XY: 24043 AN XY: 74316

African (AFR) AF: 0.658 AC: 27279 AN: 41476

American (AMR) AF: 0.204 AC: 3109 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.224 AC: 778 AN: 3468

East Asian (EAS) AF: 0.190 AC: 978 AN: 5156

South Asian (SAS) AF: 0.285 AC: 1375 AN: 4822

European-Finnish (FIN) AF: 0.172 AC: 1817 AN: 10574

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.204 AC: 13873 AN: 67984

Other (OTH) AF: 0.290 AC: 612 AN: 2110

Alfa AF: 0.222 Hom.: 2777

Bravo AF: 0.343

Asia WGS AF: 0.260 AC: 902 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.2
DANN	Benign	0.45
PhyloP100		-0.80
PromoterAI		-0.068	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs3743204; hg19: chr15-55790310; COSMIC: COSV58249893;