17-46171644-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_015443.4(KANSL1):c.500A>C(p.His167Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000712 in 1,404,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H167R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: KANSL1 NM_015443.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.07

Genes affected

KANSL1 (HGNC:24565): (KAT8 regulatory NSL complex subunit 1) This gene encodes a nuclear protein that is a subunit of two protein complexes involved with histone acetylation, the MLL1 complex and the NSL1 complex. The encoded protein has been implicated in a variety of cellular processes including enhancer regulation, cell proliferation, and mitosis. Mutations in this gene are associated with Koolen-de Vries Syndrome. [provided by RefSeq, May 2022]

ACMG classification

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=0.13725495).
• BP6: Variant 17-46171644-T-G is Benign according to our data. Variant chr17-46171644-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 380345.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KANSL1	NM_015443.4	c.500A>C	p.His167Pro	missense_variant	2/15	ENST00000432791.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KANSL1	ENST00000432791.7	c.500A>C	p.His167Pro	missense_variant	2/15	1	NM_015443.4	P4

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD3 exomes AF: 0.00000496 AC: 1 AN: 201436 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 107942

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000411

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: 7.12e-7 AC: 1 AN: 1404870 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 694916

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000300

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 Cov.: 35

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 04, 2015

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	21
Dann	Benign	0.90
Eigen	Benign	-0.21
Eigen_PC	Benign	0.028
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.14	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	0.65	D;D;N;N;N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.32	N;.;.;.;.;N;.;.;.
REVEL	Benign	0.17
Sift	Benign	0.28	T;.;.;.;.;T;.;.;.
Sift4G	Benign	0.22	T;T;T;.;T;T;.;.;.
Vest4		0.57
MutPred		0.098		Gain of glycosylation at S165 (P = 0.0507);Gain of glycosylation at S165 (P = 0.0507);Gain of glycosylation at S165 (P = 0.0507);Gain of glycosylation at S165 (P = 0.0507);Gain of glycosylation at S165 (P = 0.0507);Gain of glycosylation at S165 (P = 0.0507);Gain of glycosylation at S165 (P = 0.0507);Gain of glycosylation at S165 (P = 0.0507);Gain of glycosylation at S165 (P = 0.0507);
MVP		0.50
MPC		0.019
ClinPred		0.11	T
GERP RS		5.0
gMVP		0.16

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: rs779594202; hg19: chr17-44249010;