7-138837928-G-A

Variant summary

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

The NM_001164665.2(KIAA1549):c.5831C>T(p.Thr1944Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,462 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T1944T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: KIAA1549 NM_001164665.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.03

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11758575).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIAA1549	NM_001164665.2	c.5831C>T	p.Thr1944Ile	missense_variant	20/20	ENST00000422774.2
KIAA1549	NM_020910.3	c.5783C>T	p.Thr1928Ile	missense_variant	20/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIAA1549	ENST00000422774.2	c.5831C>T	p.Thr1944Ile	missense_variant	20/20	1	NM_001164665.2	A2
KIAA1549	ENST00000440172.5	c.5783C>T	p.Thr1928Ile	missense_variant	20/20	1		P4
TMEM213	ENST00000413208.1	c.214G>A	p.Val72Met	missense_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461462 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726982

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: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 20, 2021

This sequence change replaces threonine with isoleucine at codon 1944 of the KIAA1549 protein (p.Thr1944Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with KIAA1549-related conditions. This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.72	T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	0.82	N;N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.059
Sift	Benign	0.074	T;T
Sift4G	Benign	0.14	T;T
Polyphen		0.59	P;P
Vest4		0.065
MutPred		0.20		.;Loss of ubiquitination at K1941 (P = 0.0468);
MVP		0.093
MPC		0.13
ClinPred		0.83	D
GERP RS		4.7
Varity_R		0.080
gMVP		0.33

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: rs1370272885; hg19: chr7-138522673; COSMIC: COSV54327296;