11-95025682-A-G

Variant names:

• chr11-95025682-A-G
• rs2257265
• NM_001161630.1:c.125A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001161630.1(KDM4E):​c.125A>G​(p.Gln42Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00249 in 1,548,226 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (50 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (30 hom.)
• Consequence: KDM4E NM_001161630.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.52
• Publications: 5 publications found

Genes affected

KDM4E (HGNC:37098): (lysine demethylase 4E) The protein encoded by this intronless gene is a member of a large family of histone lysine demethylases, which use oxygen and 2-oxoglutarate to demethylate di- and trimethylated lys9 of histone H3. Derepression of genes by demethylases is sometimes involved in viral infection or carcinogenesis, so inhibitors of these enzymes are desired. [provided by RefSeq, Dec 2016]

ENSG00000299693 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020182133).
• BP6: Variant 11-95025682-A-G is Benign according to our data. Variant chr11-95025682-A-G is described in ClinVar as Benign. ClinVar VariationId is 781030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0115 (1741/151246) while in subpopulation AFR AF = 0.0386 (1594/41250). AF 95% confidence interval is 0.0371. There are 50 homozygotes in GnomAd4. There are 851 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 50 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001161630.1. 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
	KDM4E	NM_001161630.1	MANE Select	c.125A>G	p.Gln42Arg	missense	Exon 1 of 1	NP_001155102.1	B2RXH2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM4E	ENST00000450979.2	TSL:6 MANE Select	c.125A>G	p.Gln42Arg	missense	Exon 1 of 1	ENSP00000397239.2	B2RXH2
	ENSG00000299693	ENST00000765628.1		n.192+11977T>C		intron	N/A
	ENSG00000299693	ENST00000765629.1		n.175+11982T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1741 AN: 151128 Hom.: 50 Cov.: 33

Gnomad AFR AF: 0.0388

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00495

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000422

Gnomad FIN AF: 0.000285

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000649

Gnomad OTH AF: 0.00625

GnomAD2 exomes AF: 0.00325 AC: 543 AN: 167088 AF XY: 0.00275

Gnomad AFR exome AF: 0.0387

Gnomad AMR exome AF: 0.00360

Gnomad ASJ exome AF: 0.00280

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000458

Gnomad OTH exome AF: 0.00319

GnomAD4 exome AF: 0.00151 AC: 2108 AN: 1396980 Hom.: 30 Cov.: 35 AF XY: 0.00138 AC XY: 956 AN XY: 690848

African (AFR) AF: 0.0363 AC: 1156 AN: 31802

American (AMR) AF: 0.00410 AC: 156 AN: 38020

Ashkenazi Jewish (ASJ) AF: 0.00306 AC: 78 AN: 25462

East Asian (EAS) AF: 0.0000542 AC: 2 AN: 36876

South Asian (SAS) AF: 0.000162 AC: 13 AN: 80226

European-Finnish (FIN) AF: 0.000300 AC: 11 AN: 36632

Middle Eastern (MID) AF: 0.00263 AC: 15 AN: 5712

European-Non Finnish (NFE) AF: 0.000460 AC: 499 AN: 1083906

Other (OTH) AF: 0.00305 AC: 178 AN: 58344

GnomAD4 genome AF: 0.0115 AC: 1741 AN: 151246 Hom.: 50 Cov.: 33 AF XY: 0.0115 AC XY: 851 AN XY: 73898

African (AFR) AF: 0.0386 AC: 1594 AN: 41250

American (AMR) AF: 0.00494 AC: 75 AN: 15170

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 9 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5054

South Asian (SAS) AF: 0.000423 AC: 2 AN: 4730

European-Finnish (FIN) AF: 0.000285 AC: 3 AN: 10514

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000649 AC: 44 AN: 67762

Other (OTH) AF: 0.00618 AC: 13 AN: 2102

Alfa AF: 0.00923 Hom.: 11

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0412 AC: 57

ESP6500EA AF: 0.00126 AC: 4

ExAC AF: 0.00319 AC: 377

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.046
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.0080
DANN	Benign	0.097
DEOGEN2	Benign	0.0016	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0020	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-2.7	N
PhyloP100		1.5
PrimateAI	Benign	0.38	T
PROVEAN	Benign	3.0	N
REVEL	Benign	0.041
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.052
MVP		0.043
MPC		0.38
ClinPred		0.0051	T
GERP RS		0.20
PromoterAI		0.024	Neutral
Varity_R		0.083
gMVP		0.087
Mutation Taster		=89/11	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: rs2257265; hg19: chr11-94758846; COSMIC: COSV104442311; COSMIC: COSV104442311;