15-36892298-C-A

Variant names:

• chr15-36892298-C-A
• rs374458760
• NM_170675.5:c.1309G>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_170675.5(MEIS2):​c.1309G>T​(p.Ala437Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MEIS2 NM_170675.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.25

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the MEIS2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 14 curated pathogenic missense variants (we use a threshold of 10). The gene has 6 curated benign missense variants. Gene score misZ: 2.4571 (below the threshold of 3.09). Trascript score misZ: 3.4197 (above the threshold of 3.09). GenCC associations: The gene is linked to syndromic intellectual disability, cardiac malformation, cleft lip/palate, microcephaly, and digital anomalies.
• BP4: Computational evidence support a benign effect (MetaRNN=0.17635795).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEIS2	NM_170675.5	c.1309G>T	p.Ala437Ser	missense_variant	Exon 12 of 12	ENST00000561208.6	NP_733775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEIS2	ENST00000561208.6	c.1309G>T	p.Ala437Ser	missense_variant	Exon 12 of 12	1	NM_170675.5	ENSP00000453793.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	23
DANN	Benign	0.93
DEOGEN2	Benign	0.12	T;.
Eigen	Benign	-0.11
Eigen_PC	Benign	0.089
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.18	T;T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	1.4	L;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.48	N;N
REVEL	Uncertain	0.35
Sift	Benign	0.35	T;T
Sift4G	Benign	0.77	T;T
Polyphen		0.11	B;B
Vest4		0.36
MutPred		0.24		Gain of phosphorylation at A437 (P = 0.0295);.;
MVP		0.57
MPC		0.0079
ClinPred		0.56	D
GERP RS		4.8
Varity_R		0.083
gMVP		0.43

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: rs374458760; hg19: chr15-37184499;