6-24596250-T-G

Variant names:

• chr6-24596250-T-G
• rs4576240
• NM_014809.4:c.424A>C

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.424A>C​(p.Thr142Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.907 in 1,614,112 control chromosomes in the GnomAD database, including 664,946 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. T142S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.91 (63527 hom., cov: 33)
  • Exomes 𝑓: 0.91 (601419 hom.)
• Consequence: KIAA0319 NM_014809.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.800
• Publications: 40 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=5.99598E-7).
• BP6: Variant 6-24596250-T-G is Benign according to our data. Variant chr6-24596250-T-G is described in ClinVar as Benign. ClinVar VariationId is 3059261.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.963 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.424A>C	p.Thr142Pro	missense	Exon 3 of 21	NP_055624.2	Q5VV43-1
	KIAA0319	NM_001168375.2		c.424A>C	p.Thr142Pro	missense	Exon 3 of 21	NP_001161847.1	Q5VV43-1
	KIAA0319	NM_001350403.2		c.424A>C	p.Thr142Pro	missense	Exon 3 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.424A>C	p.Thr142Pro	missense	Exon 3 of 21	ENSP00000367459.3	Q5VV43-1
	KIAA0319	ENST00000537886.5	TSL:1	c.424A>C	p.Thr142Pro	missense	Exon 3 of 19	ENSP00000439700.1	Q5VV43-4
	KIAA0319	ENST00000901508.1		c.424A>C	p.Thr142Pro	missense	Exon 3 of 21	ENSP00000571567.1

Frequencies

GnomAD3 genomes AF: 0.913 AC: 138902 AN: 152144 Hom.: 63466 Cov.: 33

Gnomad AFR AF: 0.925

Gnomad AMI AF: 0.766

Gnomad AMR AF: 0.935

Gnomad ASJ AF: 0.917

Gnomad EAS AF: 0.986

Gnomad SAS AF: 0.936

Gnomad FIN AF: 0.918

Gnomad MID AF: 0.889

Gnomad NFE AF: 0.894

Gnomad OTH AF: 0.908

GnomAD2 exomes AF: 0.918 AC: 230511 AN: 251126 AF XY: 0.916

Gnomad AFR exome AF: 0.927

Gnomad AMR exome AF: 0.952

Gnomad ASJ exome AF: 0.911

Gnomad EAS exome AF: 0.992

Gnomad FIN exome AF: 0.909

Gnomad NFE exome AF: 0.892

Gnomad OTH exome AF: 0.916

GnomAD4 exome AF: 0.907 AC: 1325577 AN: 1461850 Hom.: 601419 Cov.: 69 AF XY: 0.907 AC XY: 659254 AN XY: 727232

African (AFR) AF: 0.924 AC: 30932 AN: 33478

American (AMR) AF: 0.950 AC: 42466 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.910 AC: 23788 AN: 26134

East Asian (EAS) AF: 0.977 AC: 38794 AN: 39700

South Asian (SAS) AF: 0.936 AC: 80762 AN: 86254

European-Finnish (FIN) AF: 0.906 AC: 48371 AN: 53404

Middle Eastern (MID) AF: 0.867 AC: 5003 AN: 5768

European-Non Finnish (NFE) AF: 0.900 AC: 1000273 AN: 1111992

Other (OTH) AF: 0.914 AC: 55188 AN: 60396

GnomAD4 genome AF: 0.913 AC: 139022 AN: 152262 Hom.: 63527 Cov.: 33 AF XY: 0.916 AC XY: 68193 AN XY: 74432

African (AFR) AF: 0.926 AC: 38464 AN: 41552

American (AMR) AF: 0.935 AC: 14300 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.917 AC: 3183 AN: 3470

East Asian (EAS) AF: 0.986 AC: 5099 AN: 5172

South Asian (SAS) AF: 0.936 AC: 4515 AN: 4824

European-Finnish (FIN) AF: 0.918 AC: 9751 AN: 10618

Middle Eastern (MID) AF: 0.888 AC: 261 AN: 294

European-Non Finnish (NFE) AF: 0.894 AC: 60836 AN: 68016

Other (OTH) AF: 0.909 AC: 1919 AN: 2112

Alfa AF: 0.899 Hom.: 288498

Bravo AF: 0.915

TwinsUK AF: 0.909 AC: 3369

ALSPAC AF: 0.902 AC: 3477

ESP6500AA AF: 0.921 AC: 4057

ESP6500EA AF: 0.896 AC: 7704

ExAC AF: 0.914 AC: 111013

Asia WGS AF: 0.960 AC: 3340 AN: 3478

EpiCase AF: 0.897

EpiControl AF: 0.888

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	0.035
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	16
DANN	Benign	0.56
DEOGEN2	Benign	0.00059	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.064	T
MetaRNN	Benign	6.0e-7	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-2.0	N
PhyloP100		0.80
PrimateAI	Benign	0.43	T
PROVEAN	Benign	1.6	N
REVEL	Benign	0.039
Sift	Benign	1.0	T
Sift4G	Benign	0.81	T
Polyphen		0.0	B
Vest4		0.072
MPC		0.14
ClinPred		0.0012	T
GERP RS		2.5
Varity_R		0.12
gMVP		0.25
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs4576240; hg19: chr6-24596478; COSMIC: COSV65500941; COSMIC: COSV65500941;