15-55466995-T-C

Variant names:

• chr15-55466995-T-C
• rs600753
• NM_130810.4:c.572A>G

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.572A>G​(p.Glu191Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.517 in 1,580,218 control chromosomes in the GnomAD database, including 215,443 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E191Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.48 (18831 hom., cov: 32)
  • Exomes 𝑓: 0.52 (196612 hom.)
• Consequence: DNAAF4 NM_130810.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.27
• Publications: 46 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 (MetaRNN=1.2143059E-6).
• BP6: Variant 15-55466995-T-C is Benign according to our data. Variant chr15-55466995-T-C is described in ClinVar as Benign. ClinVar VariationId is 262315.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.724 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAAF4	NM_130810.4	c.572A>G	p.Glu191Gly	missense_variant	Exon 5 of 10	ENST00000321149.7	NP_570722.2
DNAAF4	NM_001033560.2	c.572A>G	p.Glu191Gly	missense_variant	Exon 5 of 9		NP_001028732.1
DNAAF4	NM_001033559.3	c.572A>G	p.Glu191Gly	missense_variant	Exon 5 of 9		NP_001028731.1
DNAAF4-CCPG1	NR_037923.1	n.827A>G		non_coding_transcript_exon_variant	Exon 4 of 16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAAF4	ENST00000321149.7	c.572A>G	p.Glu191Gly	missense_variant	Exon 5 of 10	1	NM_130810.4	ENSP00000323275.3

Frequencies

GnomAD3 genomes AF: 0.484 AC: 73377 AN: 151740 Hom.: 18816 Cov.: 32

Gnomad AFR AF: 0.314

Gnomad AMI AF: 0.467

Gnomad AMR AF: 0.624

Gnomad ASJ AF: 0.562

Gnomad EAS AF: 0.745

Gnomad SAS AF: 0.543

Gnomad FIN AF: 0.559

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.515

Gnomad OTH AF: 0.518

GnomAD2 exomes AF: 0.565 AC: 122158 AN: 216136 AF XY: 0.558

Gnomad AFR exome AF: 0.324

Gnomad AMR exome AF: 0.738

Gnomad ASJ exome AF: 0.567

Gnomad EAS exome AF: 0.766

Gnomad FIN exome AF: 0.565

Gnomad NFE exome AF: 0.524

Gnomad OTH exome AF: 0.559

GnomAD4 exome AF: 0.520 AC: 743283 AN: 1428360 Hom.: 196612 Cov.: 36 AF XY: 0.520 AC XY: 369290 AN XY: 709884

African (AFR) AF: 0.311 AC: 9639 AN: 30994

American (AMR) AF: 0.720 AC: 26628 AN: 37006

Ashkenazi Jewish (ASJ) AF: 0.558 AC: 14054 AN: 25168

East Asian (EAS) AF: 0.744 AC: 29084 AN: 39078

South Asian (SAS) AF: 0.536 AC: 42340 AN: 78986

European-Finnish (FIN) AF: 0.557 AC: 29395 AN: 52728

Middle Eastern (MID) AF: 0.533 AC: 2940 AN: 5518

European-Non Finnish (NFE) AF: 0.508 AC: 558456 AN: 1099996

Other (OTH) AF: 0.522 AC: 30747 AN: 58886

GnomAD4 genome AF: 0.483 AC: 73419 AN: 151858 Hom.: 18831 Cov.: 32 AF XY: 0.490 AC XY: 36380 AN XY: 74236

African (AFR) AF: 0.314 AC: 13007 AN: 41470

American (AMR) AF: 0.625 AC: 9529 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.562 AC: 1949 AN: 3468

East Asian (EAS) AF: 0.744 AC: 3836 AN: 5156

South Asian (SAS) AF: 0.543 AC: 2616 AN: 4822

European-Finnish (FIN) AF: 0.559 AC: 5850 AN: 10456

Middle Eastern (MID) AF: 0.548 AC: 161 AN: 294

European-Non Finnish (NFE) AF: 0.515 AC: 34948 AN: 67918

Other (OTH) AF: 0.520 AC: 1097 AN: 2110

Alfa AF: 0.514 Hom.: 85065

Bravo AF: 0.487

TwinsUK AF: 0.493 AC: 1829

ALSPAC AF: 0.516 AC: 1990

ESP6500AA AF: 0.314 AC: 1360

ESP6500EA AF: 0.521 AC: 4448

ExAC AF: 0.543 AC: 65369

Asia WGS AF: 0.628 AC: 2172 AN: 3456

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Nov 28, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Primary ciliary dyskinesia 25 Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.012	.;.;T;T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.46	T;T;T;.
MetaRNN	Benign	0.0000012	T;T;T;T
MetaSVM	Benign	-0.95	T
PhyloP100		1.3
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.4	N;N;N;D
REVEL	Benign	0.061
Sift	Benign	0.081	T;D;D;D
Sift4G	Uncertain	0.035	D;D;D;D
Polyphen		0.021	B;B;B;B
Vest4		0.18
MPC		0.054
ClinPred		0.010	T
GERP RS		2.5
Varity_R		0.10
gMVP		0.32
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: rs600753; hg19: chr15-55759193; COSMIC: COSV107353699;