7-138918536-T-A

Position:

chr7-138918536-T-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001164665.2(KIAA1549):c.1090A>T(p.Thr364Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,514 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T364A) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

KIAA1549
NM_001164665.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.44

Variant links:

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]

KIAA1549 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.023483187).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIAA1549	NM_001164665.2 linkuse as main transcript	c.1090A>T	p.Thr364Ser	missense_variant	2/20	ENST00000422774.2
KIAA1549	NM_020910.3 linkuse as main transcript	c.1090A>T	p.Thr364Ser	missense_variant	2/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIAA1549	ENST00000422774.2 linkuse as main transcript	c.1090A>T	p.Thr364Ser	missense_variant	2/20	1	NM_001164665.2	A2	Q9HCM3-1
KIAA1549	ENST00000440172.5 linkuse as main transcript	c.1090A>T	p.Thr364Ser	missense_variant	2/20	1		P4	Q9HCM3-2

Frequencies

GnomAD3 genomes

AF:

0.0000989

AC:

AN:

151688

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000363

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000201

AC:

AN:

249292

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135238

show subpopulations

Gnomad AFR exome

AF:

0.000323

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461710

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727136

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000988

AC:

AN:

151804

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

74182

show subpopulations

Gnomad4 AFR

AF:

0.000362

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 15, 2022

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 output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 1056666). This variant has not been reported in the literature in individuals affected with KIAA1549-related conditions. This variant is present in population databases (rs59985563, gnomAD 0.03%). This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 364 of the KIAA1549 protein (p.Thr364Ser). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.74

CADD

Benign

0.0040

DANN

Benign

0.65

DEOGEN2

Benign

0.0071

.;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.052

LIST_S2

Benign

0.24

T;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.023

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.0

L;L

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.82

N;N

REVEL

Benign

0.010

Sift

Benign

0.32

T;T

Sift4G

Benign

0.58

T;T

Polyphen

0.017

B;B

Vest4

0.039

MutPred

0.18

Gain of phosphorylation at T364 (P = 0.0519);Gain of phosphorylation at T364 (P = 0.0519);

MVP

0.15

MPC

0.092

ClinPred

0.011

GERP RS

-2.7

Varity_R

0.031

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over