rs1075938

Variant names:

• chr15-55498493-G-A
• rs1075938
• NM_130810.4:c.-164C>T

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.-164C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0345 in 920,258 control chromosomes in the GnomAD database, including 2,345 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.087 (1445 hom., cov: 30)
  • Exomes 𝑓: 0.024 (900 hom.)
• Consequence: DNAAF4 NM_130810.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0740
• Publications: 14 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=-0.82).
• BP6: Variant 15-55498493-G-A is Benign according to our data. Variant chr15-55498493-G-A is described in ClinVar as Benign. ClinVar VariationId is 1280260.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.264 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAAF4	NM_130810.4	c.-164C>T		5_prime_UTR_variant	Exon 2 of 10	ENST00000321149.7	NP_570722.2
DNAAF4-CCPG1	NR_037923.1	n.92C>T		non_coding_transcript_exon_variant	Exon 1 of 16
DNAAF4	NM_001033560.2	c.-164C>T		5_prime_UTR_variant	Exon 2 of 9		NP_001028732.1
DNAAF4	NM_001033559.3	c.-164C>T		5_prime_UTR_variant	Exon 2 of 9		NP_001028731.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAAF4	ENST00000321149.7	c.-164C>T		5_prime_UTR_variant	Exon 2 of 10	1	NM_130810.4	ENSP00000323275.3

Frequencies

GnomAD3 genomes AF: 0.0864 AC: 12940 AN: 149822 Hom.: 1440 Cov.: 30

Gnomad AFR AF: 0.268

Gnomad AMI AF: 0.0144

Gnomad AMR AF: 0.0266

Gnomad ASJ AF: 0.00697

Gnomad EAS AF: 0.00923

Gnomad SAS AF: 0.0153

Gnomad FIN AF: 0.0297

Gnomad MID AF: 0.00323

Gnomad NFE AF: 0.0151

Gnomad OTH AF: 0.0594

GnomAD4 exome AF: 0.0243 AC: 18739 AN: 770308 Hom.: 900 Cov.: 11 AF XY: 0.0233 AC XY: 8996 AN XY: 386238

African (AFR) AF: 0.290 AC: 5258 AN: 18138

American (AMR) AF: 0.0208 AC: 327 AN: 15722

Ashkenazi Jewish (ASJ) AF: 0.00943 AC: 129 AN: 13680

East Asian (EAS) AF: 0.00606 AC: 154 AN: 25412

South Asian (SAS) AF: 0.0175 AC: 895 AN: 51060

European-Finnish (FIN) AF: 0.0321 AC: 866 AN: 26992

Middle Eastern (MID) AF: 0.0374 AC: 91 AN: 2430

European-Non Finnish (NFE) AF: 0.0168 AC: 9802 AN: 582174

Other (OTH) AF: 0.0351 AC: 1217 AN: 34700

GnomAD4 genome AF: 0.0865 AC: 12978 AN: 149950 Hom.: 1445 Cov.: 30 AF XY: 0.0849 AC XY: 6201 AN XY: 73050

African (AFR) AF: 0.268 AC: 10975 AN: 40942

American (AMR) AF: 0.0266 AC: 398 AN: 14942

Ashkenazi Jewish (ASJ) AF: 0.00697 AC: 24 AN: 3444

East Asian (EAS) AF: 0.00925 AC: 46 AN: 4972

South Asian (SAS) AF: 0.0153 AC: 72 AN: 4692

European-Finnish (FIN) AF: 0.0297 AC: 300 AN: 10096

Middle Eastern (MID) AF: 0.00694 AC: 2 AN: 288

European-Non Finnish (NFE) AF: 0.0151 AC: 1022 AN: 67576

Other (OTH) AF: 0.0601 AC: 126 AN: 2096

Alfa AF: 0.0446 Hom.: 382

Bravo AF: 0.0948

Asia WGS AF: 0.0420 AC: 145 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

- -

Dec 17, 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	-0.82
CADD	Benign	7.4
DANN	Benign	0.81
PhyloP100		0.074
PromoterAI		0.089	Neutral
Mutation Taster		=300/0	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: rs1075938; hg19: chr15-55790691;