7-73840121-CTGTG-CTGTGTG

Variant names:

• chr7-73840121-C-CTG
• rs375025208
• NM_152559.3:c.389-3_389-2dupCA

Variant summary

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

The NM_152559.3(METTL27):​c.389-3_389-2dupCA variant causes a splice acceptor, intron 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 NM_152559.3 splice_acceptor, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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_benign. 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. 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 VariationId is 403605.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 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 GnomAdExome4. There are 949 alleles in the male GnomAdExome4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

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

Ensembl

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

GnomAD2 exomes AF: 0.00166 AC: 351 AN: 211532 AF XY: 0.00160

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 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

African (AFR) AF: 0.000362 AC: 11 AN: 30396

American (AMR) AF: 0.000698 AC: 27 AN: 38692

Ashkenazi Jewish (ASJ) AF: 0.0396 AC: 947 AN: 23924

East Asian (EAS) AF: 0.00 AC: 0 AN: 36244

South Asian (SAS) AF: 0.000337 AC: 26 AN: 77108

European-Finnish (FIN) AF: 0.000611 AC: 29 AN: 47444

Middle Eastern (MID) AF: 0.0183 AC: 100 AN: 5458

European-Non Finnish (NFE) AF: 0.000524 AC: 542 AN: 1035276

Other (OTH) AF: 0.00416 AC: 230 AN: 55346

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

African (AFR) AF: 0.000243 AC: 7 AN: 28814

American (AMR) AF: 0.00142 AC: 14 AN: 9884

Ashkenazi Jewish (ASJ) AF: 0.0551 AC: 174 AN: 3156

East Asian (EAS) AF: 0.00 AC: 0 AN: 3156

South Asian (SAS) AF: 0.000726 AC: 2 AN: 2756

European-Finnish (FIN) AF: 0.000324 AC: 2 AN: 6168

Middle Eastern (MID) AF: 0.0103 AC: 2 AN: 194

European-Non Finnish (NFE) AF: 0.00129 AC: 70 AN: 54428

Other (OTH) AF: 0.00603 AC: 9 AN: 1492

Alfa AF: 0.00315 Hom.: 2

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1
Mutation Taster		=92/8	polymorphism

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; COSMIC: COSV52895585;