Variant 19-47414719-G-C details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001301059.2(MEIS3):c.595C>G(p.Gln199Glu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,445,086 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

MEIS3
NM_001301059.2 missense, splice_region

Scores

Splicing: ADA: 0.8158

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.88

Variant links:

Genes affected

MEIS3 (HGNC:29537): (Meis homeobox 3) This gene encodes a homeobox protein and probable transcriptional regulator. The orthologous protein in mouse controls expression of 3-phosphoinositide dependent protein kinase 1, which promotes survival of pancreatic beta-cells. [provided by RefSeq, Sep 2016]

MEIS3 links:

MEIS3 (HGNC:):

MEIS3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
MEIS3	NM_001301059.2 linkuse as main transcript	c.595C>G	p.Gln199Glu	missense_variant, splice_region_variant	6/13	ENST00000558555.6	NP_001287988.1	Q99687-1A0A024R0W2Q49A38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEIS3	ENST00000558555.6 linkuse as main transcript	c.595C>G	p.Gln199Glu	missense_variant, splice_region_variant	6/13	5	NM_001301059.2	ENSP00000454073.1		Q99687-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.92e-7

AC:

AN:

1445086

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

717400

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.05e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 17, 2023

The c.595C>G (p.Q199E) alteration is located in exon 6 (coding exon 6) of the MEIS3 gene. This alteration results from a C to G substitution at nucleotide position 595, causing the glutamine (Q) at amino acid position 199 to be replaced by a glutamic acid (E). 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

Benign

0.077

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.039

.;.;.;.;.;T;.

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.88

D;D;D;D;.;D;D

M_CAP

Benign

0.034

MetaRNN

Uncertain

0.52

D;D;D;D;D;D;D

MetaSVM

Uncertain

0.13

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.7

N;N;.;N;N;N;N

REVEL

Uncertain

0.52

Sift

Uncertain

0.026

D;D;.;D;D;D;D

Sift4G

Benign

0.34

T;T;T;T;T;T;T

Polyphen

0.019

B;.;.;.;P;B;P

Vest4

0.36

MutPred

0.24

.;.;.;.;Loss of catalytic residue at Q199 (P = 0.0665);Loss of catalytic residue at Q199 (P = 0.0665);Loss of catalytic residue at Q199 (P = 0.0665);

MVP

0.91

MPC

0.20

ClinPred

0.97

GERP RS

3.8

Varity_R

0.23

gMVP

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.82

dbscSNV1_RF

Benign

0.49

SpliceAI score (max)

0.17

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over