NM_130810.4:c.271G>A

Variant names:

• chr15-55497712-C-T
• rs17819126
• NM_130810.4:c.271G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BA1

The NM_130810.4(DNAAF4):​c.271G>A​(p.Val91Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0606 in 1,599,962 control chromosomes in the GnomAD database, including 3,360 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V91F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.046 (234 hom., cov: 32)
  • Exomes 𝑓: 0.062 (3126 hom.)
• Consequence: DNAAF4 NM_130810.4 missense, splice_region
• Scores: Splicing: ADA: 0.9572
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.76
• Publications: 42 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 -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_RF.
• BP6: Variant 15-55497712-C-T is Benign according to our data. Variant chr15-55497712-C-T is described in ClinVar as Benign. ClinVar VariationId is 416509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0666 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAAF4	NM_130810.4	c.271G>A	p.Val91Ile	missense_variant, splice_region_variant	Exon 3 of 10	ENST00000321149.7	NP_570722.2
DNAAF4	NM_001033560.2	c.271G>A	p.Val91Ile	missense_variant, splice_region_variant	Exon 3 of 9		NP_001028732.1
DNAAF4	NM_001033559.3	c.271G>A	p.Val91Ile	missense_variant, splice_region_variant	Exon 3 of 9		NP_001028731.1
DNAAF4-CCPG1	NR_037923.1	n.526G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAAF4	ENST00000321149.7	c.271G>A	p.Val91Ile	missense_variant, splice_region_variant	Exon 3 of 10	1	NM_130810.4	ENSP00000323275.3

Frequencies

GnomAD3 genomes AF: 0.0460 AC: 6998 AN: 152034 Hom.: 235 Cov.: 32

Gnomad AFR AF: 0.0145

Gnomad AMI AF: 0.204

Gnomad AMR AF: 0.0379

Gnomad ASJ AF: 0.0467

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0367

Gnomad FIN AF: 0.0508

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0682

Gnomad OTH AF: 0.0489

GnomAD2 exomes AF: 0.0472 AC: 11324 AN: 239708 AF XY: 0.0496

Gnomad AFR exome AF: 0.0114

Gnomad AMR exome AF: 0.0322

Gnomad ASJ exome AF: 0.0427

Gnomad EAS exome AF: 0.000169

Gnomad FIN exome AF: 0.0533

Gnomad NFE exome AF: 0.0641

Gnomad OTH exome AF: 0.0564

GnomAD4 exome AF: 0.0621 AC: 89973 AN: 1447810 Hom.: 3126 Cov.: 31 AF XY: 0.0618 AC XY: 44503 AN XY: 719800

African (AFR) AF: 0.00995 AC: 324 AN: 32574

American (AMR) AF: 0.0327 AC: 1335 AN: 40814

Ashkenazi Jewish (ASJ) AF: 0.0428 AC: 1093 AN: 25516

East Asian (EAS) AF: 0.000303 AC: 12 AN: 39556

South Asian (SAS) AF: 0.0452 AC: 3763 AN: 83224

European-Finnish (FIN) AF: 0.0551 AC: 2934 AN: 53246

Middle Eastern (MID) AF: 0.0398 AC: 227 AN: 5698

European-Non Finnish (NFE) AF: 0.0693 AC: 76782 AN: 1107422

Other (OTH) AF: 0.0586 AC: 3503 AN: 59760

GnomAD4 genome AF: 0.0460 AC: 7000 AN: 152152 Hom.: 234 Cov.: 32 AF XY: 0.0444 AC XY: 3304 AN XY: 74380

African (AFR) AF: 0.0146 AC: 607 AN: 41500

American (AMR) AF: 0.0378 AC: 578 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0467 AC: 162 AN: 3468

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5174

South Asian (SAS) AF: 0.0361 AC: 174 AN: 4814

European-Finnish (FIN) AF: 0.0508 AC: 538 AN: 10594

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0683 AC: 4641 AN: 68000

Other (OTH) AF: 0.0483 AC: 102 AN: 2110

Alfa AF: 0.0547 Hom.: 759

Bravo AF: 0.0440

TwinsUK AF: 0.0655 AC: 243

ALSPAC AF: 0.0701 AC: 270

ESP6500AA AF: 0.0137 AC: 60

ESP6500EA AF: 0.0700 AC: 601

ExAC AF: 0.0477 AC: 5792

Asia WGS AF: 0.0150 AC: 53 AN: 3478

EpiCase AF: 0.0640

EpiControl AF: 0.0642

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

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

- -

Feb 11, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25525159, 19901951) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.00078	.;.;T;T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.080
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.58	T;T;T;.
MetaRNN	Benign	0.0017	T;T;T;T
MetaSVM	Benign	-1.1	T
PhyloP100		1.8
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.13	N;N;N;N
REVEL	Benign	0.039
Sift	Benign	0.51	T;T;T;T
Sift4G	Benign	0.45	T;T;T;T
Polyphen		0.0050	B;B;B;B
Vest4		0.12
MPC		0.041
ClinPred		0.011	T
GERP RS		4.7
Varity_R		0.029
gMVP		0.10
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.96
dbscSNV1_RF	Benign	0.58
SpliceAI score (max)		0.62		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.62		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs17819126; hg19: chr15-55789910; COSMIC: COSV58248715;