5-138381576-G-C

Variant names:

• chr5-138381576-G-C
• rs6865472
• NM_016604.4:c.766G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_016604.4(KDM3B):​c.766G>C​(p.Ala256Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A256V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: KDM3B NM_016604.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.678
• Publications: 30 publications found

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 Gene-Disease associations (from GenCC):

• Diets-Jongmans syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Illumina
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.058407664).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016604.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM3B	NM_016604.4	MANE Select	c.766G>C	p.Ala256Pro	missense	Exon 6 of 24	NP_057688.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM3B	ENST00000314358.10	TSL:1 MANE Select	c.766G>C	p.Ala256Pro	missense	Exon 6 of 24	ENSP00000326563.5	Q7LBC6-1
	KDM3B	ENST00000510866.5	TSL:1	n.574G>C		non_coding_transcript_exon	Exon 5 of 24	ENSP00000425186.1	H0Y9V5
	KDM3B	ENST00000938919.1		c.766G>C	p.Ala256Pro	missense	Exon 6 of 24	ENSP00000608978.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	0.24
DANN	Benign	0.96
DEOGEN2	Benign	0.0092	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.16	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.058	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.68
PrimateAI	Benign	0.30	T
PROVEAN	Benign	1.2	N
REVEL	Benign	0.071
Sift	Benign	0.26	T
Sift4G	Benign	0.29	T
Polyphen		0.021	B
Vest4		0.27
MutPred		0.25		Gain of glycosylation at A256 (P = 0.0169)
MVP		0.61
MPC		0.74
ClinPred		0.044	T
GERP RS		-2.8
Varity_R		0.038
gMVP		0.19
Mutation Taster		=98/2	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: rs6865472; hg19: chr5-137717265;