rs1172357940

Variant names:

• chr15-55430717-C-G
• rs1172357940
• NM_130810.4:c.1216G>C

Your query was ambiguous. Multiple possible variants found:

• chr15-55430717-C-G
• chr15-55430717-C-A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_130810.4(DNAAF4):​c.1216G>C​(p.Ala406Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: DNAAF4 NM_130810.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.75
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.754

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.1216G>C	p.Ala406Pro	missense	Exon 10 of 10	NP_570722.2	Q8WXU2-1
	DNAAF4	NM_001033559.3		c.1110G>C	p.Met370Ile	missense	Exon 9 of 9	NP_001028731.1	Q8WXU2-3
	DNAAF4	NM_001033560.2		c.1047+4188G>C		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.1216G>C	p.Ala406Pro	missense	Exon 10 of 10	ENSP00000323275.3	Q8WXU2-1
	DNAAF4	ENST00000457155.6	TSL:1	c.1110G>C	p.Met370Ile	missense	Exon 8 of 8	ENSP00000402640.2	Q8WXU2-3
	DNAAF4	ENST00000448430.6	TSL:1	c.1047+4188G>C		intron	N/A	ENSP00000403412.2	Q8WXU2-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74330

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Benign	-0.0039	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.018	T
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-1.1	T
PhyloP100		2.7
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.14
Sift	Benign	0.055	T
Sift4G	Uncertain	0.020	D
Polyphen		1.0	D
Vest4		0.61
MutPred		0.70		Gain of catalytic residue at A406 (P = 0.1181)
MVP		0.47
MPC		0.33
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.78
gMVP		0.70
Mutation Taster		=76/24	polymorphism

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: rs1172357940; hg19: chr15-55722915;