chr7-73840121-CTGTG-C

Position:

• chr7-73840121-CTGTG-C

Variant summary

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

The ENST00000297873.9(METTL27):​c.389-5_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 0.000615 in 1,460,134 control chromosomes in the GnomAD database, including 55 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 0.0000090 (0 hom., cov: 26)
  • Exomes 𝑓: 0.00066 (55 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 7.4, offset of 0 (no position change), new splice context is: ccacccccccccacacacAGgga. 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 55 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
METTL27	NM_152559.3	c.389-5_389-2del		splice_acceptor_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000297873.9	NP_689772.2
METTL27	XM_017011777.2	c.389-5_389-2del		splice_acceptor_variant, splice_polypyrimidine_tract_variant, intron_variant			XP_016867266.1
METTL27	XM_017011778.2	c.389-5_389-2del		splice_acceptor_variant, splice_polypyrimidine_tract_variant, intron_variant			XP_016867267.1
METTL27	XR_001744563.2	n.420-5_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.389-5_389-2del		splice_acceptor_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_152559.3	ENSP00000297873	P1
METTL27	ENST00000458679.5	c.253-5_253-2del		splice_acceptor_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		4		ENSP00000398533
METTL27	ENST00000493174.1	n.284-5_284-2del		splice_acceptor_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00000903 AC: 1 AN: 110800 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000184

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00308 AC: 652 AN: 211532 Hom.: 45 AF XY: 0.00311 AC XY: 355 AN XY: 114074

Gnomad AFR exome AF: 0.00221

Gnomad AMR exome AF: 0.00190

Gnomad ASJ exome AF: 0.000739

Gnomad EAS exome AF: 0.00614

Gnomad SAS exome AF: 0.00796

Gnomad FIN exome AF: 0.00243

Gnomad NFE exome AF: 0.00237

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000665 AC: 897 AN: 1349334 Hom.: 55 AF XY: 0.000701 AC XY: 469 AN XY: 668576

Gnomad4 AFR exome AF: 0.000296

Gnomad4 AMR exome AF: 0.00124

Gnomad4 ASJ exome AF: 0.000125

Gnomad4 EAS exome AF: 0.00171

Gnomad4 SAS exome AF: 0.00242

Gnomad4 FIN exome AF: 0.000822

Gnomad4 NFE exome AF: 0.000506

Gnomad4 OTH exome AF: 0.000470

GnomAD4 genome AF: 0.00000903 AC: 1 AN: 110800 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 52408

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000184

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000340 Hom.: 2

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;