5-138352820-G-A

Position:

• chr5-138352820-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_016604.4(KDM3B):​c.25G>A​(p.Val9Met) variant causes a missense change. The variant allele was found at a frequency of 0.000000848 in 1,179,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.5e-7 (0 hom.)
• Consequence: KDM3B NM_016604.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.45

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.30937964).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KDM3B	NM_016604.4	c.25G>A	p.Val9Met	missense_variant	1/24	ENST00000314358.10	NP_057688.3
KDM3B	XM_047417313.1	c.-1024G>A		5_prime_UTR_premature_start_codon_gain_variant	1/25		XP_047273269.1
KDM3B	XM_005272018.5	c.25G>A	p.Val9Met	missense_variant	1/23		XP_005272075.1
KDM3B	XM_047417313.1	c.-1024G>A		5_prime_UTR_variant	1/25		XP_047273269.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KDM3B	ENST00000314358.10	c.25G>A	p.Val9Met	missense_variant	1/24	1	NM_016604.4	ENSP00000326563.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.48e-7 AC: 1 AN: 1179920 Hom.: 0 Cov.: 34 AF XY: 0.00000173 AC XY: 1 AN XY: 577332

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000371

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 08, 2024

Variant summary: KDM3B c.25G>A (p.Val9Met) results in a conservative amino acid change located in the Domain of unknown function (DUF7030) (IPR054294) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. To our knowledge, no occurrence of c.25G>A in individuals affected with KDM3B-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.015	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.93	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.90	L
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.11
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.70	P
Vest4		0.31
MutPred		0.37		Gain of ubiquitination at K11 (P = 0.1108);
MVP		0.26
MPC		1.3
ClinPred		0.93	D
GERP RS		3.8
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.9
Varity_R		0.31
gMVP		0.39

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: rs1437771298; hg19: chr5-137688509;