7-73840121-CTGTG-CTGTGTG

Position:

• chr7-73840121-CTGTG-CTGTGTG

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 4P and 10B. PVS1_Strong BP6_Moderate BS1 BS2

The ENST00000297873.9(METTL27):​c.389-2_389-1insCA variant causes a splice acceptor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0015 in 1,460,744 control chromosomes in the GnomAD database, including 19 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0025 (4 hom., cov: 27)
  • Exomes 𝑓: 0.0014 (15 hom.)
• Consequence: METTL27 ENST00000297873.9 splice_acceptor
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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 Likely_benign. Variant got -6 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 3.1, offset of 0 (no position change), new splice context is: ccccccacacacacacacAGgga. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• BP6: Variant 7-73840121-C-CTG is Benign according to our data. Variant chr7-73840121-C-CTG is described in ClinVar as [Likely_benign]. Clinvar id is 403605.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00142 (1912/1349888) while in subpopulation MID AF= 0.0183 (100/5458). AF 95% confidence interval is 0.0154. There are 15 homozygotes in gnomad4_exome. There are 949 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00254 AC: 281 AN: 110796 Hom.: 4 Cov.: 27

Gnomad AFR AF: 0.000244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00142

Gnomad ASJ AF: 0.0551

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000725

Gnomad FIN AF: 0.000324

Gnomad MID AF: 0.0143

Gnomad NFE AF: 0.00129

Gnomad OTH AF: 0.00602

GnomAD3 exomes AF: 0.00166 AC: 351 AN: 211532 Hom.: 5 AF XY: 0.00160 AC XY: 183 AN XY: 114074

Gnomad AFR exome AF: 0.000267

Gnomad AMR exome AF: 0.000610

Gnomad ASJ exome AF: 0.0265

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000350

Gnomad FIN exome AF: 0.000406

Gnomad NFE exome AF: 0.000878

Gnomad OTH exome AF: 0.00232

GnomAD4 exome AF: 0.00142 AC: 1912 AN: 1349888 Hom.: 15 Cov.: 34 AF XY: 0.00142 AC XY: 949 AN XY: 668946

Gnomad4 AFR exome AF: 0.000362

Gnomad4 AMR exome AF: 0.000698

Gnomad4 ASJ exome AF: 0.0396

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000337

Gnomad4 FIN exome AF: 0.000611

Gnomad4 NFE exome AF: 0.000524

Gnomad4 OTH exome AF: 0.00416

GnomAD4 genome AF: 0.00253 AC: 280 AN: 110856 Hom.: 4 Cov.: 27 AF XY: 0.00227 AC XY: 119 AN XY: 52468

Gnomad4 AFR AF: 0.000243

Gnomad4 AMR AF: 0.00142

Gnomad4 ASJ AF: 0.0551

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000726

Gnomad4 FIN AF: 0.000324

Gnomad4 NFE AF: 0.00129

Gnomad4 OTH AF: 0.00603

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Not reported. No information available. Gene not associated to pt disease. -

Computational scores

Source: dbNSFP v4.3

Splicing

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;