rs1809788517

Variant names:

• chr7-138837994-T-C
• rs1809788517
• NM_001164665.2:c.5765A>G

Variant summary

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

The NM_001164665.2(KIAA1549):​c.5765A>G​(p.His1922Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KIAA1549 NM_001164665.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.22

Genes affected

KIAA1549 (HGNC:22219): (KIAA1549) The protein encoded by this gene belongs to the UPF0606 family. This gene has been found to be fused to the BRAF oncogene in many cases of pilocytic astrocytoma. The fusion results from 2Mb tandem duplications at 7q34. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2012]

TMEM213 (HGNC:27220): (transmembrane protein 213) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

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 rank	MANE	Protein	UniProt
KIAA1549	NM_001164665.2	c.5765A>G	p.His1922Arg	missense_variant	Exon 20 of 20	ENST00000422774.2	NP_001158137.1
KIAA1549	NM_020910.3	c.5717A>G	p.His1906Arg	missense_variant	Exon 20 of 20		NP_065961.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIAA1549	ENST00000422774.2	c.5765A>G	p.His1922Arg	missense_variant	Exon 20 of 20	1	NM_001164665.2	ENSP00000416040.2
KIAA1549	ENST00000440172.5	c.5717A>G	p.His1906Arg	missense_variant	Exon 20 of 20	1		ENSP00000406661.1
TMEM213	ENST00000413208.1	c.280T>C	p.Trp94Arg	missense_variant	Exon 3 of 3	3		ENSP00000401570.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

May 22, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with KIAA1549-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 1922 of the KIAA1549 protein (p.His1922Arg). ClinVar contains an entry for this variant (Variation ID: 1513642). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.080	.;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Uncertain	0.098	D
MetaRNN	Uncertain	0.47	T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.1	.;M
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-4.6	D;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0070	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.52
MutPred		0.35		.;Gain of MoRF binding (P = 0.0224);
MVP		0.25
MPC		0.56
ClinPred		0.98	D
GERP RS		5.6
Varity_R		0.71
gMVP		0.52

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: rs1809788517; hg19: chr7-138522739;