7-73840121-CTGTG-CTGTGTGTG

Variant names:

• chr7-73840121-C-CTGTG
• rs375025208
• NM_152559.3:c.389-5_389-2dupCACA

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.12
• Publications: 4 publications found

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]

ACMG classification

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152559.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	METTL27	NM_152559.3	MANE Select	c.389-5_389-2dupCACA		splice_acceptor intron	N/A	NP_689772.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	METTL27	ENST00000297873.9	TSL:1 MANE Select	c.389-2_389-1insCACA		splice_acceptor intron	N/A	ENSP00000297873.4
	METTL27	ENST00000458679.5	TSL:4	n.253-2_253-1insCACA		splice_acceptor intron	N/A	ENSP00000398533.1
	METTL27	ENST00000493174.1	TSL:2	n.284-2_284-1insCACA		splice_acceptor intron	N/A

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1350360 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 669174

African (AFR) AF: 0.00 AC: 0 AN: 30414

American (AMR) AF: 0.00 AC: 0 AN: 38696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23948

East Asian (EAS) AF: 0.00 AC: 0 AN: 36260

South Asian (SAS) AF: 0.00 AC: 0 AN: 77132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47470

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5460

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1035598

Other (OTH) AF: 0.00 AC: 0 AN: 55382

GnomAD4 genome Cov.: 27

Alfa AF: 0.00 Hom.: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1

Splicing

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

Other links and lift over

dbSNP: rs375025208; hg19: chr7-73254451;