Genetic Variant METTL27:c.389-3_389-2delCA (chr7-73840121-CTG-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PVS1_StrongBS2

The NM_152559.3(METTL27):c.389-3_389-2delCA variant causes a splice acceptor, splice region, 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
NM_152559.3 splice_acceptor, splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.12

Publications

4 publications found

Variant links:

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]

METTL27 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 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 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

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

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

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
METTL27	ENST00000297873.9	TSL:1 MANE Select	c.389-3_389-2delCA	splice_acceptor splice_region intron	N/A	ENSP00000297873.4	Q8N6F8
METTL27	ENST00000866837.1		c.389-3_389-2delCA	splice_acceptor splice_region intron	N/A	ENSP00000536896.1
METTL27	ENST00000866839.1		c.389-3_389-2delCA	splice_acceptor splice_region intron	N/A	ENSP00000536898.1

Frequencies

GnomAD3 genomes

AF:

0.000433

AC:

AN:

110794

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00118

AC:

249

AN:

211532

AF XY:

0.00110

show subpopulations

Gnomad AFR exome

AF:

0.00308

Gnomad AMR exome

AF:

0.000897

Gnomad ASJ exome

AF:

0.000123

Gnomad EAS exome

AF:

0.00373

Gnomad FIN exome

AF:

0.000463

Gnomad NFE exome

AF:

0.000648

Gnomad OTH exome

AF:

0.00116

GnomAD4 exome

AF:

0.000432

AC:

583

AN:

1348188

Hom.:

AF XY:

0.000488

AC XY:

326

AN XY:

668064

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000988

AC:

AN:

30358

American (AMR)

AF:

0.00122

AC:

AN:

38620

Ashkenazi Jewish (ASJ)

AF:

0.0000418

AC:

AN:

23906

East Asian (EAS)

AF:

0.00199

AC:

AN:

36166

South Asian (SAS)

AF:

0.00159

AC:

122

AN:

76912

European-Finnish (FIN)

AF:

0.000317

AC:

AN:

47370

Middle Eastern (MID)

AF:

0.000367

AC:

AN:

5456

European-Non Finnish (NFE)

AF:

0.000260

AC:

269

AN:

1034122

Other (OTH)

AF:

0.000452

AC:

AN:

55278

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.386

Heterozygous variant carriers

110

138

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000433

AC:

AN:

110854

Hom.:

Cov.:

AF XY:

0.000400

AC XY:

AN XY:

52464

show subpopulations

African (AFR)

AF:

0.000104

AC:

AN:

28812

American (AMR)

AF:

0.00273

AC:

AN:

9880

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3158

East Asian (EAS)

AF:

0.00253

AC:

AN:

3156

South Asian (SAS)

AF:

0.000363

AC:

AN:

2756

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6170

Middle Eastern (MID)

AF:

0.00

AC:

AN:

194

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

54428

Other (OTH)

AF:

0.000670

AC:

AN:

1492

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00102

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.1

Mutation Taster

=83/17

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

7-73840121-CTGTG-CTG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over