rs35631512

Variant names:

• chr11-94998437-C-G
• rs35631512
• NM_018039.3:c.1065C>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_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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (29 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (43 hom.)
• Consequence: KDM4D NM_018039.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.768
• Publications: 4 publications found

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]

ENSG00000299693 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 29 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018039.3. 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
	KDM4D	NM_018039.3	MANE Select	c.1065C>G	p.Ser355Arg	missense	Exon 3 of 3	NP_060509.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM4D	ENST00000335080.6	TSL:1 MANE Select	c.1065C>G	p.Ser355Arg	missense	Exon 3 of 3	ENSP00000334181.5	Q6B0I6
	KDM4D	ENST00000536741.1	TSL:4	c.1065C>G	p.Ser355Arg	missense	Exon 2 of 2	ENSP00000460897.1	Q6B0I6
	KDM4D	ENST00000610872.1	TSL:6	c.1065C>G	p.Ser355Arg	missense	Exon 1 of 1	ENSP00000482224.1	Q6B0I6

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1757 AN: 152178 Hom.: 29 Cov.: 32

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

GnomAD2 exomes AF: 0.00307 AC: 769 AN: 250706 AF XY: 0.00220

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 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.: 43 Cov.: 32 AF XY: 0.00108 AC XY: 785 AN XY: 726998

African (AFR) AF: 0.0430 AC: 1439 AN: 33480

American (AMR) AF: 0.00208 AC: 93 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52920

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5768

European-Non Finnish (NFE) AF: 0.0000396 AC: 44 AN: 1111998

Other (OTH) AF: 0.00335 AC: 202 AN: 60386

GnomAD4 genome AF: 0.0116 AC: 1761 AN: 152296 Hom.: 29 Cov.: 32 AF XY: 0.0115 AC XY: 858 AN XY: 74478

African (AFR) AF: 0.0406 AC: 1688 AN: 41558

American (AMR) AF: 0.00314 AC: 48 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68034

Other (OTH) AF: 0.00663 AC: 14 AN: 2112

Alfa AF: 0.00180 Hom.: 2

Bravo AF: 0.0131

ESP6500AA AF: 0.0423 AC: 186

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00389 AC: 472

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000237

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	0.11
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.32
DANN	Benign	0.96
DEOGEN2	Benign	0.26	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.36	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		-0.77
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.023
Sift	Benign	0.13	T
Sift4G	Uncertain	0.058	T
Polyphen		0.016	B
Vest4		0.083
MutPred		0.10		Gain of MoRF binding (P = 0.0291)
MVP		0.13
MPC		0.66
ClinPred		0.0032	T
GERP RS		-2.8
Varity_R		0.14
gMVP		0.47
Mutation Taster		=100/0	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: rs35631512; hg19: chr11-94731601; COSMIC: COSV99075204;