rs4504469

chr6-24588656-C-Gchr6-24588656-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014809.4(KIAA0319):c.931G>C(p.Ala311Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,461,800 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A311T) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: KIAA0319 NM_014809.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.51

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0827041).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIAA0319	NM_014809.4	c.931G>C	p.Ala311Pro	missense_variant	4/21	ENST00000378214.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIAA0319	ENST00000378214.8	c.931G>C	p.Ala311Pro	missense_variant	4/21	1	NM_014809.4	P2
KIAA0319	ENST00000537886.5	c.931G>C	p.Ala311Pro	missense_variant	4/19	1
KIAA0319	ENST00000535378.5	c.904G>C	p.Ala302Pro	missense_variant	5/22	2		A2
KIAA0319	ENST00000430948.6	c.796G>C	p.Ala266Pro	missense_variant	3/20	2		A2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251386 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135864

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: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461800 Hom.: 0 Cov.: 38 AF XY: 0.0000261 AC XY: 19 AN XY: 727210

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: 0.0000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	0.27
Dann	Benign	0.93
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.26	T;T;T;.;T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.083	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.54	N;N;N;N;N
REVEL	Benign	0.088
Sift	Benign	0.14	T;T;T;T;T
Sift4G	Benign	0.27	T;T;T;T;T
Polyphen		0.95, 0.91	.;.;P;P;P
Vest4		0.10
MutPred		0.20		.;Gain of glycosylation at A311 (P = 0.0113);.;Gain of glycosylation at A311 (P = 0.0113);Gain of glycosylation at A311 (P = 0.0113);
MVP		0.20
MPC		0.31
ClinPred		0.16	T
GERP RS		-4.6
Varity_R		0.048
gMVP		0.29

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: rs4504469; hg19: chr6-24588884;