NM_004973.4:c.269C>G

Variant names:

• chr6-15410311-C-G
• rs1765823535
• NM_004973.4:c.269C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_004973.4(JARID2):​c.269C>G​(p.Ser90Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S90F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: JARID2 NM_004973.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.19
• Publications: 0 publications found

Genes affected

JARID2 (HGNC:6196): (jumonji and AT-rich interaction domain containing 2) This gene encodes a Jumonji- and AT-rich interaction domain (ARID)-domain-containing protein. The encoded protein is a DNA-binding protein that functions as a transcriptional repressor. This protein interacts with the Polycomb repressive complex 2 (PRC2) which plays an essential role in regulating gene expression during embryonic development. This protein facilitates the recruitment of the PRC2 complex to target genes. Alternate splicing results in multiple transcript variants. Mutations in this gene are associated with chronic myeloid malignancies. [provided by RefSeq, May 2012]

JARID2 Gene-Disease associations (from GenCC):

• developmental delay with variable intellectual disability and dysmorphic facies

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000309943 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.30109465).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004973.4. 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
	JARID2	NM_004973.4	MANE Select	c.269C>G	p.Ser90Cys	missense	Exon 3 of 18	NP_004964.2
	JARID2	NM_001267040.1		c.-248C>G		5_prime_UTR_premature_start_codon_gain	Exon 3 of 18	NP_001253969.1	Q92833-3
	JARID2	NM_001267040.1		c.-248C>G		5_prime_UTR	Exon 3 of 18	NP_001253969.1	Q92833-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JARID2	ENST00000341776.7	TSL:1 MANE Select	c.269C>G	p.Ser90Cys	missense	Exon 3 of 18	ENSP00000341280.2	Q92833-1
	JARID2	ENST00000397311.4	TSL:2	c.-248C>G		5_prime_UTR_premature_start_codon_gain	Exon 3 of 18	ENSP00000380478.3	Q92833-3
	JARID2	ENST00000853926.1		c.269C>G	p.Ser90Cys	missense	Exon 4 of 19	ENSP00000523985.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461788 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727206

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111928

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.5	L
PhyloP100		5.2
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.12
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.012	D
Polyphen		0.96	D
Vest4		0.42
MutPred		0.23		Loss of phosphorylation at S90 (P = 0.0083)
MVP		0.52
MPC		1.9
ClinPred		0.93	D
GERP RS		5.5
Varity_R		0.16
gMVP		0.52
Mutation Taster		=67/33	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: rs1765823535; hg19: chr6-15410542;