rs807534

Positions:

• chr6-24551436-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_014809.4(KIAA0319):​c.3038A>G​(p.Tyr1013Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.131 in 1,593,340 control chromosomes in the GnomAD database, including 14,484 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.12 (1131 hom., cov: 32)
  • Exomes 𝑓: 0.13 (13353 hom.)
• Consequence: KIAA0319 NM_014809.4 missense, splice_region
• Scores: Splicing: ADA: 0.00006375
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.66

Genes affected

KIAA0319 (HGNC:21580): (KIAA0319) This gene encodes a transmembrane protein that contains a large extracellular domain with multiple polycystic kidney disease (PKD) domains. The encoded protein may play a role in the development of the cerebral cortex by regulating neuronal migration and cell adhesion. Single nucleotide polymorphisms in this gene are associated with dyslexia. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2011]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016924143).
• BP6: Variant 6-24551436-T-C is Benign according to our data. Variant chr6-24551436-T-C is described in ClinVar as [Benign]. Clinvar id is 3060890.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIAA0319	NM_014809.4	c.3038A>G	p.Tyr1013Cys	missense_variant, splice_region_variant	20/21	ENST00000378214.8	NP_055624.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIAA0319	ENST00000378214.8	c.3038A>G	p.Tyr1013Cys	missense_variant, splice_region_variant	20/21	1	NM_014809.4	ENSP00000367459	P2

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17875 AN: 152100 Hom.: 1130 Cov.: 32

Gnomad AFR AF: 0.0952

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.0901

Gnomad ASJ AF: 0.0787

Gnomad EAS AF: 0.0820

Gnomad SAS AF: 0.113

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.113

GnomAD3 exomes AF: 0.119 AC: 29879 AN: 251242 Hom.: 1900 AF XY: 0.119 AC XY: 16220 AN XY: 135798

Gnomad AFR exome AF: 0.0936

Gnomad AMR exome AF: 0.0956

Gnomad ASJ exome AF: 0.0740

Gnomad EAS exome AF: 0.0905

Gnomad SAS exome AF: 0.115

Gnomad FIN exome AF: 0.124

Gnomad NFE exome AF: 0.138

Gnomad OTH exome AF: 0.119

GnomAD4 exome AF: 0.132 AC: 190114 AN: 1441122 Hom.: 13353 Cov.: 29 AF XY: 0.131 AC XY: 94016 AN XY: 718186

Gnomad4 AFR exome AF: 0.0901

Gnomad4 AMR exome AF: 0.0955

Gnomad4 ASJ exome AF: 0.0734

Gnomad4 EAS exome AF: 0.0593

Gnomad4 SAS exome AF: 0.112

Gnomad4 FIN exome AF: 0.126

Gnomad4 NFE exome AF: 0.141

Gnomad4 OTH exome AF: 0.130

GnomAD4 genome AF: 0.118 AC: 17897 AN: 152218 Hom.: 1131 Cov.: 32 AF XY: 0.114 AC XY: 8521 AN XY: 74424

Gnomad4 AFR AF: 0.0951

Gnomad4 AMR AF: 0.0904

Gnomad4 ASJ AF: 0.0787

Gnomad4 EAS AF: 0.0822

Gnomad4 SAS AF: 0.114

Gnomad4 FIN AF: 0.123

Gnomad4 NFE AF: 0.141

Gnomad4 OTH AF: 0.114

Alfa AF: 0.129 Hom.: 3305

Bravo AF: 0.114

TwinsUK AF: 0.147 AC: 546

ALSPAC AF: 0.148 AC: 571

ESP6500AA AF: 0.0942 AC: 415

ESP6500EA AF: 0.134 AC: 1149

ExAC AF: 0.120 AC: 14582

Asia WGS AF: 0.0960 AC: 334 AN: 3478

EpiCase AF: 0.129

EpiControl AF: 0.128

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

KIAA0319-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 23, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.030	.;.;.;T;T
Eigen	Benign	0.17
Eigen_PC	Benign	0.091
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.90	D;T;T;.;T
MetaRNN	Benign	0.0017	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	.;.;.;M;M
MutationTaster	Benign	0.13	P;P;P;P;P
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.7	.;D;D;D;D
REVEL	Benign	0.097
Sift	Benign	0.20	.;T;T;T;T
Sift4G	Benign	0.17	T;T;T;T;T
Polyphen		1.0, 1.0	.;.;D;D;D
Vest4		0.28
MPC		0.55
ClinPred		0.026	T
GERP RS		0.20
Varity_R		0.11
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000064
dbscSNV1_RF	Benign	0.040
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs807534; hg19: chr6-24551664; COSMIC: COSV65497408;