NM_014809.4:c.3038A>G

Variant names:

• chr6-24551436-T-C
• rs807534
• NM_014809.4:c.3038A>G

Variant summary

Our verdict is Benign. The variant received -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. 13/23 in silico tools predict 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).

• 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
• Publications: 26 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
KIAA0319	NM_014809.4	c.3038A>G	p.Tyr1013Cys	missense_variant, splice_region_variant	Exon 20 of 21	ENST00000378214.8	NP_055624.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIAA0319	ENST00000378214.8	c.3038A>G	p.Tyr1013Cys	missense_variant, splice_region_variant	Exon 20 of 21	1	NM_014809.4	ENSP00000367459.3

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

GnomAD2 exomes AF: 0.119 AC: 29879 AN: 251242 AF XY: 0.119

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 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

African (AFR) AF: 0.0901 AC: 2986 AN: 33148

American (AMR) AF: 0.0955 AC: 4269 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.0734 AC: 1913 AN: 26058

East Asian (EAS) AF: 0.0593 AC: 2348 AN: 39610

South Asian (SAS) AF: 0.112 AC: 9578 AN: 85886

European-Finnish (FIN) AF: 0.126 AC: 6708 AN: 53408

Middle Eastern (MID) AF: 0.0876 AC: 503 AN: 5740

European-Non Finnish (NFE) AF: 0.141 AC: 154038 AN: 1092892

Other (OTH) AF: 0.130 AC: 7771 AN: 59686

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

African (AFR) AF: 0.0951 AC: 3950 AN: 41530

American (AMR) AF: 0.0904 AC: 1382 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0787 AC: 273 AN: 3470

East Asian (EAS) AF: 0.0822 AC: 426 AN: 5182

South Asian (SAS) AF: 0.114 AC: 548 AN: 4824

European-Finnish (FIN) AF: 0.123 AC: 1302 AN: 10588

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

European-Non Finnish (NFE) AF: 0.141 AC: 9622 AN: 68020

Other (OTH) AF: 0.114 AC: 241 AN: 2114

Alfa AF: 0.129 Hom.: 5942

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

Dec 23, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
PhyloP100		1.7
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
Mutation Taster		=89/11	polymorphism (auto)

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

Other links and lift over

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