rs6865472

Positions:

• chr5-138381576-G-A
• chr5-138381576-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BA1

The NM_016604.4(KDM3B):​c.766G>A​(p.Ala256Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.997 in 1,602,284 control chromosomes in the GnomAD database, including 796,510 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.98 (73757 hom., cov: 34)
  • Exomes 𝑓: 1.0 (722753 hom.)
• Consequence: KDM3B NM_016604.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.678

Genes affected

KDM3B (HGNC:1337): (lysine demethylase 3B) Predicted to enable chromatin DNA binding activity; histone H3-methyl-lysine-9 demethylase activity; and transcription coregulator activity. Predicted to be involved in histone H3-K9 demethylation and regulation of transcription by RNA polymerase II. Located in nucleoplasm. Biomarker of acute lymphoblastic leukemia; breast cancer; colorectal cancer; and lung non-small cell carcinoma. [provided by Alliance of Genome Resources, Apr 2022]

KDM3B (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KDM3B. . Gene score misZ 4.9789 (greater than the threshold 3.09). Trascript score misZ 6.2129 (greater than threshold 3.09). GenCC has associacion of gene with Diets-Jongmans syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=8.2785095E-7).
• BP6: Variant 5-138381576-G-A is Benign according to our data. Variant chr5-138381576-G-A is described in ClinVar as [Benign]. Clinvar id is 1300057.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KDM3B	NM_016604.4	c.766G>A	p.Ala256Thr	missense_variant	6/24	ENST00000314358.10	NP_057688.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KDM3B	ENST00000314358.10	c.766G>A	p.Ala256Thr	missense_variant	6/24	1	NM_016604.4	ENSP00000326563.5
KDM3B	ENST00000510866.5	n.574G>A		non_coding_transcript_exon_variant	5/24	1		ENSP00000425186.1
KDM3B	ENST00000512928.1	n.455G>A		non_coding_transcript_exon_variant	5/5	2

Frequencies

GnomAD3 genomes AF: 0.983 AC: 149716 AN: 152236 Hom.: 73695 Cov.: 34

Gnomad AFR AF: 0.942

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.994

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.997

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.990

GnomAD3 exomes AF: 0.996 AC: 250321 AN: 251358 Hom.: 124669 AF XY: 0.997 AC XY: 135437 AN XY: 135844

Gnomad AFR exome AF: 0.944

Gnomad AMR exome AF: 0.997

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.998

GnomAD4 exome AF: 0.998 AC: 1447649 AN: 1449930 Hom.: 722753 Cov.: 32 AF XY: 0.999 AC XY: 721172 AN XY: 722106

Gnomad4 AFR exome AF: 0.944

Gnomad4 AMR exome AF: 0.997

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.997

GnomAD4 genome AF: 0.983 AC: 149838 AN: 152354 Hom.: 73757 Cov.: 34 AF XY: 0.984 AC XY: 73340 AN XY: 74504

Gnomad4 AFR AF: 0.942

Gnomad4 AMR AF: 0.994

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 1.00

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 1.00

Gnomad4 OTH AF: 0.990

Alfa AF: 0.997 Hom.: 146307

Bravo AF: 0.981

TwinsUK AF: 1.00 AC: 3708

ALSPAC AF: 1.00 AC: 3854

ESP6500AA AF: 0.948 AC: 4176

ESP6500EA AF: 1.00 AC: 8600

ExAC AF: 0.995 AC: 120818

Asia WGS AF: 0.997 AC: 3466 AN: 3478

EpiCase AF: 1.00

EpiControl AF: 1.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Diets-Jongmans syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.045
DANN	Benign	0.32
DEOGEN2	Benign	0.0099	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0061	N
LIST_S2	Benign	0.068	T
MetaRNN	Benign	8.3e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.40	N
REVEL	Benign	0.024
Sift	Benign	0.77	T
Sift4G	Benign	0.44	T
Polyphen		0.0	B
Vest4		0.034
MPC		0.55
ClinPred		0.0040	T
GERP RS		-2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.017
gMVP		0.081

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: rs6865472; hg19: chr5-137717265;