6-24596250-T-C

Variant names:

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

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014809.4(KIAA0319):​c.424A>G​(p.Thr142Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T142P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KIAA0319 NM_014809.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.800

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.038777113).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIAA0319	NM_014809.4	c.424A>G	p.Thr142Ala	missense_variant	Exon 3 of 21	ENST00000378214.8	NP_055624.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIAA0319	ENST00000378214.8	c.424A>G	p.Thr142Ala	missense_variant	Exon 3 of 21	1	NM_014809.4	ENSP00000367459.3
KIAA0319	ENST00000537886.5	c.424A>G	p.Thr142Ala	missense_variant	Exon 3 of 19	1		ENSP00000439700.1
KIAA0319	ENST00000535378.5	c.397A>G	p.Thr133Ala	missense_variant	Exon 4 of 22	2		ENSP00000442403.1
KIAA0319	ENST00000430948.6	c.289A>G	p.Thr97Ala	missense_variant	Exon 2 of 20	2		ENSP00000401086.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 69

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	14
DANN	Benign	0.65
DEOGEN2	Benign	0.00055	.;.;.;T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.13	T;T;T;.;T
M_CAP	Benign	0.00073	T
MetaRNN	Benign	0.039	T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	.;N;.;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.25	N;N;N;N;N
REVEL	Benign	0.013
Sift	Benign	0.51	T;T;T;T;T
Sift4G	Benign	0.80	T;T;T;T;T
Polyphen		0.0010, 0.0	.;.;B;B;B
Vest4		0.17
MutPred		0.25		.;Loss of ubiquitination at K139 (P = 0.0738);.;Loss of ubiquitination at K139 (P = 0.0738);Loss of ubiquitination at K139 (P = 0.0738);
MVP		0.10
MPC		0.10
ClinPred		0.083	T
GERP RS		2.5
Varity_R		0.039
gMVP		0.17

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

Publications

LitVar

Other links and lift over

dbSNP: rs4576240; hg19: chr6-24596478;