NM_130810.4:c.1259C>G

Variant names:

• chr15-55430674-G-C
• rs77641439
• NM_130810.4:c.1259C>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.1259C>G​(p.Ser420Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0969 in 1,610,990 control chromosomes in the GnomAD database, including 8,196 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.085 (585 hom., cov: 32)
  • Exomes 𝑓: 0.098 (7611 hom.)
• Consequence: DNAAF4 NM_130810.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.37
• Publications: 23 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=0.0015182495).
• BP6: Variant 15-55430674-G-C is Benign according to our data. Variant chr15-55430674-G-C is described in ClinVar as Benign. ClinVar VariationId is 262314.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.17 is higher than 0.05.

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.1259C>G	p.Ser420Cys	missense	Exon 10 of 10	NP_570722.2	Q8WXU2-1
	DNAAF4	NM_001033559.3		c.*22C>G		3_prime_UTR	Exon 9 of 9	NP_001028731.1	Q8WXU2-3
	DNAAF4	NM_001033560.2		c.1047+4231C>G		intron	N/A	NP_001028732.1	Q8WXU2-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF4	ENST00000321149.7	TSL:1 MANE Select	c.1259C>G	p.Ser420Cys	missense	Exon 10 of 10	ENSP00000323275.3	Q8WXU2-1
	DNAAF4	ENST00000457155.6	TSL:1	c.*22C>G		3_prime_UTR	Exon 8 of 8	ENSP00000402640.2	Q8WXU2-3
	DNAAF4	ENST00000448430.6	TSL:1	c.1047+4231C>G		intron	N/A	ENSP00000403412.2	Q8WXU2-2

Frequencies

GnomAD3 genomes AF: 0.0854 AC: 12978 AN: 152048 Hom.: 581 Cov.: 32

Gnomad AFR AF: 0.0666

Gnomad AMI AF: 0.115

Gnomad AMR AF: 0.0726

Gnomad ASJ AF: 0.0902

Gnomad EAS AF: 0.179

Gnomad SAS AF: 0.114

Gnomad FIN AF: 0.0573

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0943

Gnomad OTH AF: 0.0818

GnomAD2 exomes AF: 0.0914 AC: 22874 AN: 250224 AF XY: 0.0935

Gnomad AFR exome AF: 0.0663

Gnomad AMR exome AF: 0.0550

Gnomad ASJ exome AF: 0.0944

Gnomad EAS exome AF: 0.179

Gnomad FIN exome AF: 0.0613

Gnomad NFE exome AF: 0.0924

Gnomad OTH exome AF: 0.0924

GnomAD4 exome AF: 0.0981 AC: 143164 AN: 1458824 Hom.: 7611 Cov.: 31 AF XY: 0.0984 AC XY: 71393 AN XY: 725746

African (AFR) AF: 0.0600 AC: 2005 AN: 33396

American (AMR) AF: 0.0570 AC: 2536 AN: 44510

Ashkenazi Jewish (ASJ) AF: 0.0973 AC: 2534 AN: 26046

East Asian (EAS) AF: 0.204 AC: 8042 AN: 39478

South Asian (SAS) AF: 0.108 AC: 9275 AN: 85816

European-Finnish (FIN) AF: 0.0598 AC: 3177 AN: 53090

Middle Eastern (MID) AF: 0.0774 AC: 437 AN: 5644

European-Non Finnish (NFE) AF: 0.0982 AC: 109054 AN: 1110626

Other (OTH) AF: 0.101 AC: 6104 AN: 60218

GnomAD4 genome AF: 0.0854 AC: 13001 AN: 152166 Hom.: 585 Cov.: 32 AF XY: 0.0834 AC XY: 6207 AN XY: 74394

African (AFR) AF: 0.0670 AC: 2781 AN: 41508

American (AMR) AF: 0.0724 AC: 1105 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.0902 AC: 313 AN: 3470

East Asian (EAS) AF: 0.179 AC: 929 AN: 5176

South Asian (SAS) AF: 0.114 AC: 549 AN: 4822

European-Finnish (FIN) AF: 0.0573 AC: 607 AN: 10586

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0943 AC: 6412 AN: 68022

Other (OTH) AF: 0.0838 AC: 177 AN: 2112

Alfa AF: 0.0895 Hom.: 215

Bravo AF: 0.0844

TwinsUK AF: 0.109 AC: 405

ALSPAC AF: 0.0968 AC: 373

ESP6500AA AF: 0.0734 AC: 322

ESP6500EA AF: 0.0942 AC: 808

ExAC AF: 0.0918 AC: 11141

Asia WGS AF: 0.148 AC: 512 AN: 3474

EpiCase AF: 0.0957

EpiControl AF: 0.101

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0082	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.1	T
PhyloP100		3.4
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.11
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.13
MPC		0.32
ClinPred		0.022	T
GERP RS		3.5
Varity_R		0.17
gMVP		0.37
Mutation Taster		=96/4	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: rs77641439; hg19: chr15-55722872; COSMIC: COSV58247414;