7-138918536-T-C

Position:

• chr7-138918536-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001164665.2(KIAA1549):​c.1090A>G​(p.Thr364Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.203 in 1,613,426 control chromosomes in the GnomAD database, including 38,274 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (7262 hom., cov: 32)
  • Exomes 𝑓: 0.20 (31012 hom.)
• Consequence: KIAA1549 NM_001164665.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.44

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.0390105E-4).
• BP6: Variant 7-138918536-T-C is Benign according to our data. Variant chr7-138918536-T-C is described in ClinVar as [Benign]. Clinvar id is 1166981.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.5 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIAA1549	NM_001164665.2	c.1090A>G	p.Thr364Ala	missense_variant	2/20	ENST00000422774.2	NP_001158137.1
KIAA1549	NM_020910.3	c.1090A>G	p.Thr364Ala	missense_variant	2/20		NP_065961.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIAA1549	ENST00000422774.2	c.1090A>G	p.Thr364Ala	missense_variant	2/20	1	NM_001164665.2	ENSP00000416040.2
KIAA1549	ENST00000440172.5	c.1090A>G	p.Thr364Ala	missense_variant	2/20	1		ENSP00000406661.1

Frequencies

GnomAD3 genomes AF: 0.272 AC: 41307 AN: 151650 Hom.: 7242 Cov.: 32

Gnomad AFR AF: 0.505

Gnomad AMI AF: 0.179

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.168

Gnomad EAS AF: 0.138

Gnomad SAS AF: 0.312

Gnomad FIN AF: 0.158

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.183

Gnomad OTH AF: 0.246

GnomAD3 exomes AF: 0.208 AC: 51836 AN: 249292 Hom.: 6481 AF XY: 0.210 AC XY: 28369 AN XY: 135238

Gnomad AFR exome AF: 0.519

Gnomad AMR exome AF: 0.153

Gnomad ASJ exome AF: 0.169

Gnomad EAS exome AF: 0.136

Gnomad SAS exome AF: 0.304

Gnomad FIN exome AF: 0.155

Gnomad NFE exome AF: 0.182

Gnomad OTH exome AF: 0.190

GnomAD4 exome AF: 0.196 AC: 286717 AN: 1461660 Hom.: 31012 Cov.: 37 AF XY: 0.198 AC XY: 143961 AN XY: 727116

Gnomad4 AFR exome AF: 0.516

Gnomad4 AMR exome AF: 0.155

Gnomad4 ASJ exome AF: 0.165

Gnomad4 EAS exome AF: 0.133

Gnomad4 SAS exome AF: 0.306

Gnomad4 FIN exome AF: 0.158

Gnomad4 NFE exome AF: 0.184

Gnomad4 OTH exome AF: 0.209

GnomAD4 genome AF: 0.273 AC: 41378 AN: 151766 Hom.: 7262 Cov.: 32 AF XY: 0.272 AC XY: 20172 AN XY: 74164

Gnomad4 AFR AF: 0.506

Gnomad4 AMR AF: 0.183

Gnomad4 ASJ AF: 0.168

Gnomad4 EAS AF: 0.138

Gnomad4 SAS AF: 0.312

Gnomad4 FIN AF: 0.158

Gnomad4 NFE AF: 0.183

Gnomad4 OTH AF: 0.249

Alfa AF: 0.181 Hom.: 3869

Bravo AF: 0.280

TwinsUK AF: 0.193 AC: 715

ALSPAC AF: 0.176 AC: 678

ESP6500AA AF: 0.474 AC: 2043

ESP6500EA AF: 0.183 AC: 1555

ExAC AF: 0.218 AC: 26392

Asia WGS AF: 0.249 AC: 868 AN: 3478

EpiCase AF: 0.183

EpiControl AF: 0.186

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2019	- -

Retinitis pigmentosa 86 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Retinal dystrophy Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.0060
DANN	Benign	0.81
DEOGEN2	Benign	0.0092	.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.26	T;T
MetaRNN	Benign	0.00070	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.4	L;L
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.0080
Sift	Benign	0.25	T;T
Sift4G	Benign	0.13	T;T
Polyphen		0.0040	B;B
Vest4		0.018
MPC		0.098
ClinPred		0.0071	T
GERP RS		-2.7
Varity_R		0.027
gMVP		0.20

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: rs59985563; hg19: chr7-138603282; COSMIC: COSV54308739;