17-43642011-G-T

Variant names:

• chr17-43642011-G-T
• rs772798486
• ENST00000549132.2:c.491C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_013999.4(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. 12/15 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 NM_013999.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.04

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 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 Lovd as [Pathogenic].
• 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	c.664C>A	p.Arg222Arg	synonymous_variant	Exon 3 of 3	ENST00000318579.9	NP_004518.1
MEOX1	NM_013999.4	c.491C>A	p.Pro164Gln	missense_variant	Exon 2 of 2		NP_054705.1
MEOX1	NM_001040002.2	c.319C>A	p.Arg107Arg	synonymous_variant	Exon 4 of 4		NP_001035091.1
MEOX1	XM_011524818.3	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	Appris	UniProt
MEOX1	ENST00000549132.2	c.491C>A	p.Pro164Gln	missense_variant	Exon 2 of 2	1		ENSP00000449049.2
MEOX1	ENST00000318579.9	c.664C>A	p.Arg222Arg	synonymous_variant	Exon 3 of 3	1	NM_004527.4	ENSP00000321684.4
MEOX1	ENST00000393661.2	c.319C>A	p.Arg107Arg	synonymous_variant	Exon 4 of 4	3		ENSP00000377271.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000804 AC: 2 AN: 248836 Hom.: 0 AF XY: 0.00000742 AC XY: 1 AN XY: 134714

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 SAS 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: 3 AN: 1461608 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727134

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	9.7
DANN	Uncertain	0.99
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.033
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.086	T
MetaSVM	Benign	-0.92	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.013	D
Vest4		0.18
MutPred		0.084		Loss of sheet (P = 0.0457);
MVP		0.62
ClinPred		0.45	T
GERP RS		3.6

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

LitVar

Other links and lift over

dbSNP: rs772798486; hg19: chr17-41719379;