rs59985563

Variant names:

• chr7-138918536-T-A
• rs59985563
• NM_001164665.2:c.1090A>T

Your query was ambiguous. Multiple possible variants found:

• chr7-138918536-T-A
• chr7-138918536-T-C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS1

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. 16/22 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.44
• Publications: 32 publications found

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 Gene-Disease associations (from GenCC):

• retinitis pigmentosa 86

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• retinitis pigmentosa

  Inheritance: AR, AD Classification: SUPPORTIVE, LIMITED Submitted by: G2P, Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.023483187).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0000988 (15/151804) while in subpopulation AFR AF = 0.000362 (15/41424). AF 95% confidence interval is 0.000222. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164665.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIAA1549	NM_001164665.2	MANE Select	c.1090A>T	p.Thr364Ser	missense	Exon 2 of 20	NP_001158137.1	Q9HCM3-1
	KIAA1549	NM_020910.3		c.1090A>T	p.Thr364Ser	missense	Exon 2 of 20	NP_065961.2	Q9HCM3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIAA1549	ENST00000422774.2	TSL:1 MANE Select	c.1090A>T	p.Thr364Ser	missense	Exon 2 of 20	ENSP00000416040.2	Q9HCM3-1
	KIAA1549	ENST00000440172.5	TSL:1	c.1090A>T	p.Thr364Ser	missense	Exon 2 of 20	ENSP00000406661.1	Q9HCM3-2
	KIAA1549	ENST00000924635.1		c.1090A>T	p.Thr364Ser	missense	Exon 2 of 18	ENSP00000594694.1

Frequencies

GnomAD3 genomes AF: 0.0000989 AC: 15 AN: 151688 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.0000201 AC: 5 AN: 249292 AF XY: 0.00000739

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461710 Hom.: 0 Cov.: 37 AF XY: 0.00000275 AC XY: 2 AN XY: 727136

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111870

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome AF: 0.0000988 AC: 15 AN: 151804 Hom.: 0 Cov.: 32 AF XY: 0.0000674 AC XY: 5 AN XY: 74182

African (AFR) AF: 0.000362 AC: 15 AN: 41424

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10552

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67842

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.00 Hom.: 7789

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.56	T
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	N
LIST_S2	Benign	0.24	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.023	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.0	L
PhyloP100		-1.4
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.010
Sift	Benign	0.32	T
Sift4G	Benign	0.58	T
Polyphen		0.017	B
Vest4		0.039
MutPred		0.18		Gain of phosphorylation at T364 (P = 0.0519)
MVP		0.15
MPC		0.092
ClinPred		0.011	T
GERP RS		-2.7
Varity_R		0.031
gMVP		0.17
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs59985563; hg19: chr7-138603282;