12-312228-T-C

Variant names:

• chr12-312228-T-C
• rs11062357
• NM_001042603.3:c.3036+828A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001042603.3(KDM5A):​c.3036+828A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.332 in 152,070 control chromosomes in the GnomAD database, including 10,772 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.33 (10772 hom., cov: 32)
• Consequence: KDM5A NM_001042603.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00700
• Publications: 8 publications found

Genes affected

KDM5A (HGNC:9886): (lysine demethylase 5A) This gene encodes a member of the Jumonji, AT-rich interactive domain 1 (JARID1) histone demethylase protein family. The encoded protein plays a role in gene regulation through the histone code by specifically demethylating lysine 4 of histone H3. The encoded protein interacts with many other proteins, including retinoblastoma protein, and is implicated in the transcriptional regulation of Hox genes and cytokines. This gene may play a role in tumor progression. [provided by RefSeq, Aug 2013]

KDM5A Gene-Disease associations (from GenCC):

• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• neurodevelopmental disorder

  Inheritance: AD, AR Classification: LIMITED Submitted by: Ambry Genetics, G2P
• El Hayek-Chahrour neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.479 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KDM5A	NM_001042603.3	c.3036+828A>G		intron_variant	Intron 20 of 27	ENST00000399788.7	NP_001036068.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KDM5A	ENST00000399788.7	c.3036+828A>G		intron_variant	Intron 20 of 27	1	NM_001042603.3	ENSP00000382688.2
KDM5A	ENST00000544760.1	c.1893+828A>G		intron_variant	Intron 11 of 12	2		ENSP00000440622.1

Frequencies

GnomAD3 genomes AF: 0.333 AC: 50543 AN: 151950 Hom.: 10765 Cov.: 32

Gnomad AFR AF: 0.0842

Gnomad AMI AF: 0.547

Gnomad AMR AF: 0.272

Gnomad ASJ AF: 0.332

Gnomad EAS AF: 0.223

Gnomad SAS AF: 0.313

Gnomad FIN AF: 0.466

Gnomad MID AF: 0.366

Gnomad NFE AF: 0.484

Gnomad OTH AF: 0.337

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.332 AC: 50554 AN: 152070 Hom.: 10772 Cov.: 32 AF XY: 0.330 AC XY: 24520 AN XY: 74346

African (AFR) AF: 0.0840 AC: 3486 AN: 41518

American (AMR) AF: 0.271 AC: 4144 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.332 AC: 1152 AN: 3472

East Asian (EAS) AF: 0.223 AC: 1153 AN: 5170

South Asian (SAS) AF: 0.314 AC: 1515 AN: 4824

European-Finnish (FIN) AF: 0.466 AC: 4912 AN: 10540

Middle Eastern (MID) AF: 0.371 AC: 109 AN: 294

European-Non Finnish (NFE) AF: 0.484 AC: 32863 AN: 67946

Other (OTH) AF: 0.343 AC: 723 AN: 2110

Alfa AF: 0.430 Hom.: 25877

Bravo AF: 0.305

Asia WGS AF: 0.272 AC: 946 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.7
DANN	Benign	0.65
PhyloP100		0.0070
Mutation Taster		=100/0	polymorphism (auto)

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: rs11062357; hg19: chr12-421394;