Genetic Variant ENST00000549132.2:c.491C>A (chr17-43642011-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2PM5BP4_Moderate

The ENST00000549132.2(MEOX1):c.491C>A(p.Pro164Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P164L) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

MEOX1
ENST00000549132.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.04

Publications

3 publications found

Variant links:

Genes affected

MEOX1 (HGNC:7013): (mesenchyme homeobox 1) This gene encodes a member of a subfamily of non-clustered, diverged, antennapedia-like homeobox-containing genes. The encoded protein may play a role in the molecular signaling network regulating somite development. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

MEOX1 Gene-Disease associations (from GenCC):

Klippel-Feil syndrome 2, autosomal recessive
Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
isolated Klippel-Feil syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

MEOX1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-43642011-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 39508.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.085623264).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEOX1	NM_004527.4 link	c.664C>A	p.Arg222Arg	synonymous_variant	Exon 3 of 3	ENST00000318579.9	NP_004518.1	P50221-1
MEOX1	NM_013999.4 link	c.491C>A	p.Pro164Gln	missense_variant	Exon 2 of 2		NP_054705.1	P50221-2
MEOX1	NM_001040002.2 link	c.319C>A	p.Arg107Arg	synonymous_variant	Exon 4 of 4		NP_001035091.1	P50221-3
MEOX1	XM_011524818.3 link	c.675C>A	p.Thr225Thr	synonymous_variant	Exon 3 of 3		XP_011523120.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MEOX1	ENST00000549132.2 link	c.491C>A	p.Pro164Gln	missense_variant	Exon 2 of 2	1		ENSP00000449049.2	P50221-2
MEOX1	ENST00000318579.9 link	c.664C>A	p.Arg222Arg	synonymous_variant	Exon 3 of 3	1	NM_004527.4	ENSP00000321684.4	P50221-1
MEOX1	ENST00000393661.2 link	c.319C>A	p.Arg107Arg	synonymous_variant	Exon 4 of 4	3		ENSP00000377271.2	P50221-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000804

AC:

AN:

248836

AF XY:

0.00000742

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000898

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461608

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727134

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.0000224

AC:

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26108

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111854

Other (OTH)

AF:

0.00

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.033

BayesDel_noAF

Benign

-0.20

CADD

Benign

9.7

(source)

DANN

Uncertain

0.99

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.033

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.42

M_CAP

Benign

0.010

MetaRNN

Benign

0.086

MetaSVM

Benign

-0.92

PhyloP100

2.0

PROVEAN

Benign

-1.6

REVEL

Benign

0.12

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.013

Vest4

0.18

MutPred

0.084

Loss of sheet (P = 0.0457);

MVP

0.62

ClinPred

0.45

GERP RS

3.6

Mutation Taster

=51/49

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

ENST00000549132.2:c.491C>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over