11-94998437-C-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_018039.3(KDM4D):c.1065C>G(p.Ser355Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00221 in 1,613,660 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.012 ( 29 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 43 hom. )

Consequence

KDM4D
NM_018039.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.768

Variant links:

Genes affected

KDM4D (HGNC:25498): (lysine demethylase 4D) Enables histone H3-methyl-lysine-9 demethylase activity. Involved in histone H3-K9 demethylation. Acts upstream of or within several processes, including cellular response to ionizing radiation; positive regulation of chromatin binding activity; and positive regulation of double-strand break repair via nonhomologous end joining. Located in site of double-strand break. Biomarker of nephroblastoma. [provided by Alliance of Genome Resources, Apr 2022]

KDM4D links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0042580664).

BP6

Variant 11-94998437-C-G is Benign according to our data. Variant chr11-94998437-C-G is described in ClinVar as [Benign]. Clinvar id is 775297.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 = 0.0116 (1761/152296) while in subpopulation AFR AF= 0.0406 (1688/41558). AF 95% confidence interval is 0.039. There are 29 homozygotes in gnomad4. There are 858 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KDM4D	NM_018039.3 link	c.1065C>G	p.Ser355Arg	missense_variant	Exon 3 of 3	ENST00000335080.6	NP_060509.2	Q6B0I6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KDM4D	ENST00000335080.6 link	c.1065C>G	p.Ser355Arg	missense_variant	Exon 3 of 3	1	NM_018039.3	ENSP00000334181.5	Q6B0I6
KDM4D	ENST00000536741.1 link	c.1065C>G	p.Ser355Arg	missense_variant	Exon 2 of 2	4		ENSP00000460897.1	Q6B0I6
KDM4D	ENST00000610872.1 link	c.1065C>G	p.Ser355Arg	missense_variant	Exon 1 of 1	6		ENSP00000482224.1	Q6B0I6

Frequencies

GnomAD3 genomes

AF:

0.0115

AC:

1757

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0406

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00314

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00670

GnomAD3 exomes

AF:

0.00307

AC:

769

AN:

250706

Hom.:

AF XY:

0.00220

AC XY:

298

AN XY:

135570

show subpopulations

Gnomad AFR exome

AF:

0.0423

Gnomad AMR exome

AF:

0.00174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00123

AC:

1803

AN:

1461364

Hom.:

Cov.:

AF XY:

0.00108

AC XY:

785

AN XY:

726998

show subpopulations

Gnomad4 AFR exome

AF:

0.0430

Gnomad4 AMR exome

AF:

0.00208

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000396

Gnomad4 OTH exome

AF:

0.00335

GnomAD4 genome

AF:

0.0116

AC:

1761

AN:

152296

Hom.:

Cov.:

AF XY:

0.0115

AC XY:

858

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.0406

Gnomad4 AMR

AF:

0.00314

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00663

Alfa

AF:

0.00180

Hom.:

Bravo

AF:

0.0131

ESP6500AA

AF:

0.0423

AC:

186

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00389

AC:

472

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 09, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.32

DANN

Benign

0.96

DEOGEN2

Benign

0.26

T;T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.36

.;.;T

MetaRNN

Benign

0.0043

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

L;L;L

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-3.1

D;.;.

REVEL

Benign

0.023

Sift

Benign

0.13

T;.;.

Sift4G

Uncertain

0.058

T;T;T

Polyphen

0.016

B;B;B

Vest4

0.083

MutPred

0.10

Gain of MoRF binding (P = 0.0291);Gain of MoRF binding (P = 0.0291);Gain of MoRF binding (P = 0.0291);

MVP

0.13

MPC

0.66

ClinPred

0.0032

GERP RS

-2.8

Varity_R

0.14

gMVP

0.47

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over