1-43667976-A-G

Position:

• chr1-43667976-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014663.3(KDM4A):​c.1120A>G​(p.Met374Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00195 in 1,614,142 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (30 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (27 hom.)
• Consequence: KDM4A NM_014663.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0730

Genes affected

KDM4A (HGNC:22978): (lysine demethylase 4A) This gene is a member of the Jumonji domain 2 (JMJD2) family and encodes a protein containing a JmjN domain, a JmjC domain, a JD2H domain, two TUDOR domains, and two PHD-type zinc fingers. This nuclear protein functions as a trimethylation-specific demethylase, converting specific trimethylated histone residues to the dimethylated form, and as a transcriptional repressor. [provided by RefSeq, Apr 2009]

ENSG00000284989 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001976192).
• BP6: Variant 1-43667976-A-G is Benign according to our data. Variant chr1-43667976-A-G is described in ClinVar as [Benign]. Clinvar id is 782374.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 = 0.0106 (1614/152294) while in subpopulation AFR AF= 0.0371 (1542/41564). AF 95% confidence interval is 0.0356. There are 30 homozygotes in gnomad4. There are 785 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1614 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KDM4A	NM_014663.3	c.1120A>G	p.Met374Val	missense_variant	9/22	ENST00000372396.4	NP_055478.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KDM4A	ENST00000372396.4	c.1120A>G	p.Met374Val	missense_variant	9/22	1	NM_014663.3	ENSP00000361473.3
ENSG00000284989	ENST00000645057.1	n.623+4889A>G		intron_variant				ENSP00000494063.1

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 1610 AN: 152176 Hom.: 31 Cov.: 32

Gnomad AFR AF: 0.0371

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00354

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00282 AC: 710 AN: 251450 Hom.: 11 AF XY: 0.00215 AC XY: 292 AN XY: 135898

Gnomad AFR exome AF: 0.0388

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000791

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00105 AC: 1532 AN: 1461848 Hom.: 27 Cov.: 32 AF XY: 0.000888 AC XY: 646 AN XY: 727228

Gnomad4 AFR exome AF: 0.0356

Gnomad4 AMR exome AF: 0.00199

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000477

Gnomad4 OTH exome AF: 0.00286

GnomAD4 genome AF: 0.0106 AC: 1614 AN: 152294 Hom.: 30 Cov.: 32 AF XY: 0.0105 AC XY: 785 AN XY: 74486

Gnomad4 AFR AF: 0.0371

Gnomad4 AMR AF: 0.00353

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: 0.00331

Alfa AF: 0.00238 Hom.: 8

Bravo AF: 0.0121

ESP6500AA AF: 0.0347 AC: 153

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00338 AC: 411

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 30, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.3
DANN	Benign	0.79
DEOGEN2	Benign	0.0077	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.43	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.018
Sift	Benign	0.52	T
Sift4G	Benign	0.34	T
Polyphen		0.0	B
Vest4		0.097
MVP		0.12
MPC		0.60
ClinPred		0.00021	T
GERP RS		-0.0085
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.019
gMVP		0.42

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: rs74070653; hg19: chr1-44133647;