2-66441435-T-A

Position:

• chr2-66441435-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002398.3(MEIS1):​c.454T>A​(p.Leu152Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MEIS1 NM_002398.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.12

Genes affected

MEIS1 (HGNC:7000): (Meis homeobox 1) Homeobox genes, of which the most well-characterized category is represented by the HOX genes, play a crucial role in normal development. In addition, several homeoproteins are involved in neoplasia. This gene encodes a homeobox protein belonging to the TALE ('three amino acid loop extension') family of homeodomain-containing proteins. [provided by RefSeq, Jul 2008]

MEIS1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEIS1	NM_002398.3	c.454T>A	p.Leu152Ile	missense_variant	5/13	ENST00000272369.14	NP_002389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEIS1	ENST00000272369.14	c.454T>A	p.Leu152Ile	missense_variant	5/13	1	NM_002398.3	ENSP00000272369.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2021

The c.454T>A (p.L152I) alteration is located in exon 5 (coding exon 5) of the MEIS1 gene. This alteration results from a T to A substitution at nucleotide position 454, causing the leucine (L) at amino acid position 152 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	.;T;T;.;T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D
M_CAP	Benign	0.064	D
MetaRNN	Uncertain	0.63	D;D;D;D;D
MetaSVM	Benign	-0.47	T
MutationAssessor	Pathogenic	3.1	.;M;.;.;.
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-1.8	N;N;.;N;N
REVEL	Benign	0.26
Sift	Uncertain	0.0020	D;D;.;D;D
Sift4G	Uncertain	0.0050	D;D;D;D;T
Polyphen		1.0, 0.0060, 1.0	.;D;.;B;D
Vest4		0.70
MutPred		0.49		Gain of helix (P = 0.0349);Gain of helix (P = 0.0349);Gain of helix (P = 0.0349);.;.;
MVP		0.50
MPC		2.3
ClinPred		0.99	D
GERP RS		6.2
Varity_R		0.54
gMVP		0.86

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: rs1671978928; hg19: chr2-66668567;