7-73840121-CTGTG-CTG

Position:

• chr7-73840121-CTGTG-CTG

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PVS1_Strong BS2

The ENST00000297873.9(METTL27):​c.389-3_389-2del variant causes a splice acceptor, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000432 in 1,459,042 control chromosomes in the GnomAD database, including 9 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 27)
  • Exomes 𝑓: 0.00043 (9 hom.)
• Consequence: METTL27 ENST00000297873.9 splice_acceptor, splice_polypyrimidine_tract, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.12

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.12059621 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.1, offset of 0 (no position change), new splice context is: acccccccccacacacacAGgga. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
METTL27	NM_152559.3	c.389-3_389-2del		splice_acceptor_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000297873.9	NP_689772.2
METTL27	XM_017011777.2	c.389-3_389-2del		splice_acceptor_variant, splice_polypyrimidine_tract_variant, intron_variant			XP_016867266.1
METTL27	XM_017011778.2	c.389-3_389-2del		splice_acceptor_variant, splice_polypyrimidine_tract_variant, intron_variant			XP_016867267.1
METTL27	XR_001744563.2	n.420-3_420-2del		splice_acceptor_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
METTL27	ENST00000297873.9	c.389-3_389-2del		splice_acceptor_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_152559.3	ENSP00000297873	P1
METTL27	ENST00000458679.5	c.253-3_253-2del		splice_acceptor_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		4		ENSP00000398533
METTL27	ENST00000493174.1	n.284-3_284-2del		splice_acceptor_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.000433 AC: 48 AN: 110794 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.000104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00274

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00253

Gnomad SAS AF: 0.000362

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000668

GnomAD4 exome AF: 0.000432 AC: 583 AN: 1348188 Hom.: 9 AF XY: 0.000488 AC XY: 326 AN XY: 668064

Gnomad4 AFR exome AF: 0.000988

Gnomad4 AMR exome AF: 0.00122

Gnomad4 ASJ exome AF: 0.0000418

Gnomad4 EAS exome AF: 0.00199

Gnomad4 SAS exome AF: 0.00159

Gnomad4 FIN exome AF: 0.000317

Gnomad4 NFE exome AF: 0.000260

Gnomad4 OTH exome AF: 0.000452

GnomAD4 genome AF: 0.000433 AC: 48 AN: 110854 Hom.: 0 Cov.: 27 AF XY: 0.000400 AC XY: 21 AN XY: 52464

Gnomad4 AFR AF: 0.000104

Gnomad4 AMR AF: 0.00273

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00253

Gnomad4 SAS AF: 0.000363

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.000670

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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: rs375025208; hg19: chr7-73254451;