chr15-55418091-G-A

Variant names:

• chr15-55418091-G-A
• rs199564997
• ENST00000448430.6:c.1090C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001198784.2(PIERCE2):​c.19-132G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000142 in 1,580,710 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (2 hom.)
• Consequence: PIERCE2 NM_001198784.2 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.698
• Publications: 2 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]

PIERCE2 (HGNC:44654): (piercer of microtubule wall 2)

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0055252016).
• BS2: High Homozygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIERCE2	NM_001198784.2	c.19-132G>A		intron_variant	Intron 1 of 1	ENST00000569691.2	NP_001185713.1
DNAAF4	NM_001033560.2	c.1090C>T	p.Pro364Ser	missense_variant	Exon 9 of 9		NP_001028732.1
DNAAF4-CCPG1	NR_037923.1	n.1408+14406C>T		intron_variant	Intron 8 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIERCE2	ENST00000569691.2	c.19-132G>A		intron_variant	Intron 1 of 1	1	NM_001198784.2	ENSP00000456337.1

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000223 AC: 49 AN: 220140 AF XY: 0.000218

Gnomad AFR exome AF: 0.0000637

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00349

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000107

Gnomad OTH exome AF: 0.000188

GnomAD4 exome AF: 0.000144 AC: 205 AN: 1428522 Hom.: 2 Cov.: 28 AF XY: 0.000173 AC XY: 123 AN XY: 710242

African (AFR) AF: 0.0000317 AC: 1 AN: 31578

American (AMR) AF: 0.0000275 AC: 1 AN: 36366

Ashkenazi Jewish (ASJ) AF: 0.00462 AC: 111 AN: 24010

East Asian (EAS) AF: 0.00 AC: 0 AN: 39544

South Asian (SAS) AF: 0.000299 AC: 24 AN: 80134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52868

Middle Eastern (MID) AF: 0.000539 AC: 3 AN: 5570

European-Non Finnish (NFE) AF: 0.0000382 AC: 42 AN: 1099542

Other (OTH) AF: 0.000390 AC: 23 AN: 58910

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74346

African (AFR) AF: 0.0000241 AC: 1 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00433 AC: 15 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68038

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

Alfa AF: 0.000280 Hom.: 0

Bravo AF: 0.000196

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000222 AC: 27

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Aug 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNAAF4: PM2, BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.10
DANN	Benign	0.34
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.00037	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.00046	T
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-0.94	T
PhyloP100		-0.70
PROVEAN	Benign	1.0	N
REVEL	Benign	0.013
Sift	Benign	0.54	T
Sift4G	Benign	0.82	T
Polyphen		0.0	B
Vest4		0.060
MVP		0.11
ClinPred		0.019	T
GERP RS		-0.32
Mutation Taster		=99/1	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: rs199564997; hg19: chr15-55710289; COSMIC: COSV66207870;