rs4504469

Variant names:

• chr6-24588656-C-T
• rs4504469
• NM_014809.4:c.931G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-24588656-C-T
• chr6-24588656-C-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.931G>A​(p.Ala311Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.375 in 1,612,676 control chromosomes in the GnomAD database, including 121,819 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A311G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.29 (8414 hom., cov: 31)
  • Exomes 𝑓: 0.38 (113405 hom.)
• Consequence: KIAA0319 NM_014809.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -1.51
• Publications: 60 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=7.960599E-5).
• BP6: Variant 6-24588656-C-T is Benign according to our data. Variant chr6-24588656-C-T is described in ClinVar as Benign. ClinVar VariationId is 3056331.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.405 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014809.4. 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
	KIAA0319	NM_014809.4	MANE Select	c.931G>A	p.Ala311Thr	missense	Exon 4 of 21	NP_055624.2	Q5VV43-1
	KIAA0319	NM_001168375.2		c.931G>A	p.Ala311Thr	missense	Exon 4 of 21	NP_001161847.1	Q5VV43-1
	KIAA0319	NM_001350403.2		c.931G>A	p.Ala311Thr	missense	Exon 4 of 21	NP_001337332.1	Q5VV43-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIAA0319	ENST00000378214.8	TSL:1 MANE Select	c.931G>A	p.Ala311Thr	missense	Exon 4 of 21	ENSP00000367459.3	Q5VV43-1
	KIAA0319	ENST00000537886.5	TSL:1	c.931G>A	p.Ala311Thr	missense	Exon 4 of 19	ENSP00000439700.1	Q5VV43-4
	KIAA0319	ENST00000901508.1		c.931G>A	p.Ala311Thr	missense	Exon 4 of 21	ENSP00000571567.1

Frequencies

GnomAD3 genomes AF: 0.295 AC: 44757 AN: 151694 Hom.: 8410 Cov.: 31

Gnomad AFR AF: 0.0823

Gnomad AMI AF: 0.251

Gnomad AMR AF: 0.251

Gnomad ASJ AF: 0.376

Gnomad EAS AF: 0.130

Gnomad SAS AF: 0.298

Gnomad FIN AF: 0.517

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.409

Gnomad OTH AF: 0.280

GnomAD2 exomes AF: 0.330 AC: 83069 AN: 251386 AF XY: 0.339

Gnomad AFR exome AF: 0.0730

Gnomad AMR exome AF: 0.205

Gnomad ASJ exome AF: 0.375

Gnomad EAS exome AF: 0.133

Gnomad FIN exome AF: 0.514

Gnomad NFE exome AF: 0.404

Gnomad OTH exome AF: 0.345

GnomAD4 exome AF: 0.383 AC: 560176 AN: 1460864 Hom.: 113405 Cov.: 38 AF XY: 0.382 AC XY: 277615 AN XY: 726796

African (AFR) AF: 0.0674 AC: 2255 AN: 33474

American (AMR) AF: 0.213 AC: 9528 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.368 AC: 9628 AN: 26130

East Asian (EAS) AF: 0.124 AC: 4918 AN: 39696

South Asian (SAS) AF: 0.304 AC: 26177 AN: 86238

European-Finnish (FIN) AF: 0.510 AC: 27218 AN: 53416

Middle Eastern (MID) AF: 0.188 AC: 1081 AN: 5764

European-Non Finnish (NFE) AF: 0.412 AC: 458208 AN: 1111062

Other (OTH) AF: 0.351 AC: 21163 AN: 60360

GnomAD4 genome AF: 0.295 AC: 44776 AN: 151812 Hom.: 8414 Cov.: 31 AF XY: 0.300 AC XY: 22257 AN XY: 74160

African (AFR) AF: 0.0827 AC: 3425 AN: 41438

American (AMR) AF: 0.252 AC: 3837 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.376 AC: 1302 AN: 3466

East Asian (EAS) AF: 0.129 AC: 668 AN: 5160

South Asian (SAS) AF: 0.299 AC: 1432 AN: 4786

European-Finnish (FIN) AF: 0.517 AC: 5424 AN: 10492

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.409 AC: 27806 AN: 67904

Other (OTH) AF: 0.275 AC: 580 AN: 2108

Alfa AF: 0.357 Hom.: 21236

Bravo AF: 0.263

TwinsUK AF: 0.410 AC: 1520

ALSPAC AF: 0.403 AC: 1554

ESP6500AA AF: 0.0960 AC: 423

ESP6500EA AF: 0.404 AC: 3471

ExAC AF: 0.328 AC: 39787

Asia WGS AF: 0.216 AC: 753 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	KIAA0319-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.078
DANN	Benign	0.42
DEOGEN2	Benign	0.0011	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0024	N
LIST_S2	Benign	0.22	T
MetaRNN	Benign	0.000080	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.58	N
PhyloP100		-1.5
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.71	N
REVEL	Benign	0.0070
Sift	Benign	0.73	T
Sift4G	Benign	0.71	T
Polyphen		0.0020	B
Vest4		0.028
MPC		0.10
ClinPred		0.0055	T
GERP RS		-4.6
Varity_R		0.020
gMVP		0.15
Mutation Taster		=100/0	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: rs4504469; hg19: chr6-24588884; COSMIC: COSV65496420;