Genetic Variant METTL27:c.389-5_389-2dupCACA (chr7-73840121-C-CTGTG) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_StrongPM2

The NM_152559.3(METTL27):c.389-5_389-2dupCACA variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 27)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

METTL27
NM_152559.3 splice_acceptor, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.12

Publications

4 publications found

Variant links:

Genes affected

METTL27 (HGNC:19068): (methyltransferase like 27) This gene encodes a protein belonging to ubiE/COQ5 methyltransferase family. The gene is deleted in Williams syndrome, a multisystem developmental disorder caused by the deletion of contiguous genes at 7q11.22-q11.23. [provided by RefSeq, Jul 2008]

METTL27 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.12195122 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
METTL27	NM_152559.3 link	c.389-5_389-2dupCACA	splice_acceptor_variant, intron_variant	Intron 4 of 5	ENST00000297873.9	NP_689772.2	Q8N6F8
METTL27	XM_017011777.2 link	c.389-5_389-2dupCACA	splice_acceptor_variant, intron_variant	Intron 4 of 5		XP_016867266.1
METTL27	XM_017011778.2 link	c.389-5_389-2dupCACA	splice_acceptor_variant, intron_variant	Intron 4 of 5		XP_016867267.1
METTL27	XR_001744563.2 link	n.420-5_420-2dupCACA	splice_acceptor_variant, intron_variant	Intron 4 of 6

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
METTL27	ENST00000297873.9 link	c.389-2_389-1insCACA	splice_acceptor_variant, intron_variant	Intron 4 of 5	1	NM_152559.3	ENSP00000297873.4	Q8N6F8
METTL27	ENST00000458679.5 link	n.253-2_253-1insCACA	splice_acceptor_variant, intron_variant	Intron 3 of 4	4		ENSP00000398533.1	B4DWM3
METTL27	ENST00000493174.1 link	n.284-2_284-1insCACA	splice_acceptor_variant, intron_variant	Intron 3 of 3	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1350360

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

669174

African (AFR)

AF:

0.00

AC:

AN:

30414

American (AMR)

AF:

0.00

AC:

AN:

38696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23948

East Asian (EAS)

AF:

0.00

AC:

AN:

36260

South Asian (SAS)

AF:

0.00

AC:

AN:

77132

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47470

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5460

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1035598

Other (OTH)

AF:

0.00

AC:

AN:

55382

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.1

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over