rs4576240

chr6-24596250-T-Achr6-24596250-T-Cchr6-24596250-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014809.4(KIAA0319):c.424A>T(p.Thr142Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 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 Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• 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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIAA0319	NM_014809.4	c.424A>T	p.Thr142Ser	missense_variant	3/21	ENST00000378214.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIAA0319	ENST00000378214.8	c.424A>T	p.Thr142Ser	missense_variant	3/21	1	NM_014809.4	P2
KIAA0319	ENST00000537886.5	c.424A>T	p.Thr142Ser	missense_variant	3/19	1
KIAA0319	ENST00000535378.5	c.397A>T	p.Thr133Ser	missense_variant	4/22	2		A2
KIAA0319	ENST00000430948.6	c.289A>T	p.Thr97Ser	missense_variant	2/20	2		A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251126 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135788

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461872 Hom.: 0 Cov.: 69 AF XY: 0.00000413 AC XY: 3 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.75
Cadd	Benign	17
Dann	Benign	0.56
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.15	T;T;T;.;T
M_CAP	Benign	0.00072	T
MetaRNN	Benign	0.038	T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.46	N;N;N;N;N
REVEL	Benign	0.019
Sift	Benign	0.43	T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.0	.;.;B;B;B
Vest4		0.10
MutPred		0.25		.;Gain of disorder (P = 0.0216);.;Gain of disorder (P = 0.0216);Gain of disorder (P = 0.0216);
MVP		0.11
MPC		0.093
ClinPred		0.13	T
GERP RS		2.5
Varity_R		0.042
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.47		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.47		Position offset: -10

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;