17-46171833-T-G

Variant names:

• chr17-46171833-T-G
• rs17585974
• NM_015443.4:c.311A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_015443.4(KANSL1):​c.311A>C​(p.Lys104Thr) variant causes a missense change. The variant allele was found at a frequency of 0.151 in 1,581,184 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (0 hom., cov: 35)
  • Exomes 𝑓: 0.15 (0 hom.)
• Consequence: KANSL1 NM_015443.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 6.66
• Publications: 35 publications found

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]

KANSL1 Gene-Disease associations (from GenCC):

• Koolen-de Vries syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), ClinGen
• Koolen-de Vries syndrome due to a point mutation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015992224).
• BP6: Variant 17-46171833-T-G is Benign according to our data. Variant chr17-46171833-T-G is described in ClinVar as Benign. ClinVar VariationId is 323797.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015443.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KANSL1	NM_015443.4	MANE Select	c.311A>C	p.Lys104Thr	missense	Exon 2 of 15	NP_056258.1
	KANSL1	NM_001193466.2		c.311A>C	p.Lys104Thr	missense	Exon 2 of 15	NP_001180395.1
	KANSL1	NM_001379198.1		c.311A>C	p.Lys104Thr	missense	Exon 3 of 16	NP_001366127.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KANSL1	ENST00000432791.7	TSL:1 MANE Select	c.311A>C	p.Lys104Thr	missense	Exon 2 of 15	ENSP00000387393.3
	KANSL1	ENST00000262419.10	TSL:1	c.311A>C	p.Lys104Thr	missense	Exon 2 of 15	ENSP00000262419.6
	KANSL1	ENST00000572904.6	TSL:5	c.311A>C	p.Lys104Thr	missense	Exon 2 of 15	ENSP00000461484.1

Frequencies

GnomAD3 genomes AF: 0.115 AC: 17236 AN: 150222 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.0343

Gnomad AMI AF: 0.247

Gnomad AMR AF: 0.143

Gnomad ASJ AF: 0.181

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0513

Gnomad FIN AF: 0.0574

Gnomad MID AF: 0.172

Gnomad NFE AF: 0.174

Gnomad OTH AF: 0.150

GnomAD2 exomes AF: 0.118 AC: 29429 AN: 249468 AF XY: 0.120

Gnomad AFR exome AF: 0.0323

Gnomad AMR exome AF: 0.102

Gnomad ASJ exome AF: 0.192

Gnomad EAS exome AF: 0.000544

Gnomad FIN exome AF: 0.0608

Gnomad NFE exome AF: 0.174

Gnomad OTH exome AF: 0.144

GnomAD4 exome AF: 0.155 AC: 221562 AN: 1430848 Hom.: 0 Cov.: 35 AF XY: 0.153 AC XY: 108910 AN XY: 712762

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0300 AC: 1002 AN: 33444

American (AMR) AF: 0.108 AC: 4796 AN: 44592

Ashkenazi Jewish (ASJ) AF: 0.193 AC: 4971 AN: 25714

East Asian (EAS) AF: 0.000781 AC: 31 AN: 39696

South Asian (SAS) AF: 0.0593 AC: 5082 AN: 85644

European-Finnish (FIN) AF: 0.0667 AC: 3558 AN: 53338

Middle Eastern (MID) AF: 0.150 AC: 854 AN: 5692

European-Non Finnish (NFE) AF: 0.178 AC: 192722 AN: 1083308

Other (OTH) AF: 0.144 AC: 8546 AN: 59420

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.115 AC: 17221 AN: 150336 Hom.: 0 Cov.: 35 AF XY: 0.107 AC XY: 7894 AN XY: 73546

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0342 AC: 1417 AN: 41438

American (AMR) AF: 0.142 AC: 2144 AN: 15056

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 612 AN: 3386

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5192

South Asian (SAS) AF: 0.0509 AC: 242 AN: 4752

European-Finnish (FIN) AF: 0.0574 AC: 607 AN: 10568

Middle Eastern (MID) AF: 0.164 AC: 48 AN: 292

European-Non Finnish (NFE) AF: 0.174 AC: 11615 AN: 66676

Other (OTH) AF: 0.148 AC: 309 AN: 2082

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.154 Hom.: 987

ESP6500AA AF: 0.0384 AC: 169

ESP6500EA AF: 0.183 AC: 1576

ExAC AF: 0.120 AC: 14610

Asia WGS AF: 0.0250 AC: 86 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Koolen-de Vries syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.2	T
PhyloP100		6.7
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.021	D
Vest4		0.54
MPC		0.15
ClinPred		0.016	T
GERP RS		5.9
PromoterAI		0.022	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.48
Mutation Taster		=238/62	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: rs17585974; hg19: chr17-44249199; COSMIC: COSV52271693; COSMIC: COSV52271693;