rs879255264

Variant names:

• chr15-36896663-ATTC-A
• rs879255264
• NM_170675.5:c.998_1000delGAA

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_170675.5(MEIS2):​c.998_1000delGAA​(p.Arg333del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MEIS2 NM_170675.5 disruptive_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 7.97
• Publications: 7 publications found

Genes affected

MEIS2 (HGNC:7001): (Meis homeobox 2) This gene encodes a homeobox protein belonging to the TALE ('three amino acid loop extension') family of homeodomain-containing proteins. TALE homeobox proteins are highly conserved transcription regulators, and several members have been shown to be essential contributors to developmental programs. Multiple transcript variants encoding distinct isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

MEIS2 Gene-Disease associations (from GenCC):

• cardiac malformation, cleft lip/palate, microcephaly, and digital anomalies

  Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Illumina, Ambry Genetics
• syndromic intellectual disability

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

  Inheritance: AD Classification: STRONG Submitted by: G2P

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_170675.5
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_170675.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 15-36896663-ATTC-A is Pathogenic according to our data. Variant chr15-36896663-ATTC-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 224962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_170675.5. 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
	MEIS2	NM_170675.5	MANE Select	c.998_1000delGAA	p.Arg333del	disruptive_inframe_deletion	Exon 10 of 12	NP_733775.1	O14770-1
	MEIS2	NM_001220482.2		c.998_1000delGAA	p.Arg333del	disruptive_inframe_deletion	Exon 11 of 13	NP_001207411.1	O14770-4
	MEIS2	NM_170676.5		c.998_1000delGAA	p.Arg333del	disruptive_inframe_deletion	Exon 10 of 12	NP_733776.1	O14770-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEIS2	ENST00000561208.6	TSL:1 MANE Select	c.998_1000delGAA	p.Arg333del	disruptive_inframe_deletion	Exon 10 of 12	ENSP00000453793.1	O14770-1
	MEIS2	ENST00000338564.9	TSL:1	c.998_1000delGAA	p.Arg333del	disruptive_inframe_deletion	Exon 11 of 13	ENSP00000341400.4	O14770-4
	MEIS2	ENST00000424352.6	TSL:1	c.998_1000delGAA	p.Arg333del	disruptive_inframe_deletion	Exon 10 of 13	ENSP00000404185.2	O14770-2

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Cardiac malformation, cleft lip/palate, microcephaly, and digital anomalies (3)
2	-	-	not provided (2)
1	-	-	Cleft palate (1)
1	-	-	Inborn genetic diseases (1)
-	-	-	MEIS2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.0
Mutation Taster		=4/96	disease causing (ClinVar)

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: rs879255264; hg19: chr15-37188864;