19-47409118-C-G

Position:

• chr19-47409118-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001301059.2(MEIS3):​c.839G>C​(p.Trp280Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: MEIS3 NM_001301059.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.83

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEIS3	NM_001301059.2	c.839G>C	p.Trp280Ser	missense_variant	8/13	ENST00000558555.6	NP_001287988.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEIS3	ENST00000558555.6	c.839G>C	p.Trp280Ser	missense_variant	8/13	5	NM_001301059.2	ENSP00000454073	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

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

Jul 30, 2023

The c.839G>C (p.W280S) alteration is located in exon 8 (coding exon 8) of the MEIS3 gene. This alteration results from a G to C substitution at nucleotide position 839, causing the tryptophan (W) at amino acid position 280 to be replaced by a serine (S). 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	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	.;.;.;.;.;T;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D;.;D;D;T
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-13	D;D;.;D;D;D;D;.
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D;.;D;D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;T
Polyphen		1.0	D;.;.;.;D;D;D;.
Vest4		0.97
MutPred		0.73		.;.;.;.;Gain of disorder (P = 0.0022);Gain of disorder (P = 0.0022);Gain of disorder (P = 0.0022);.;
MVP		0.99
MPC		0.95
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.96
gMVP		0.87

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: rs751570283; hg19: chr19-47912375;