chr7-73840121-CTG-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PVS1_Strong BS2

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
• Clinical Significance: Not reported in ClinVar
• 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: 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

Selected	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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	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
	METTL27	ENST00000458679.5	TSL:4	n.253-3_253-2delCA		splice_acceptor splice_region intron	N/A	ENSP00000398533.1
	METTL27	ENST00000493174.1	TSL:2	n.284-3_284-2delCA		splice_acceptor splice_region intron	N/A

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

GnomAD2 exomes AF: 0.00118 AC: 249 AN: 211532 AF XY: 0.00110

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.: 9 AF XY: 0.000488 AC XY: 326 AN XY: 668064

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

African (AFR) AF: 0.000988 AC: 30 AN: 30358

American (AMR) AF: 0.00122 AC: 47 AN: 38620

Ashkenazi Jewish (ASJ) AF: 0.0000418 AC: 1 AN: 23906

East Asian (EAS) AF: 0.00199 AC: 72 AN: 36166

South Asian (SAS) AF: 0.00159 AC: 122 AN: 76912

European-Finnish (FIN) AF: 0.000317 AC: 15 AN: 47370

Middle Eastern (MID) AF: 0.000367 AC: 2 AN: 5456

European-Non Finnish (NFE) AF: 0.000260 AC: 269 AN: 1034122

Other (OTH) AF: 0.000452 AC: 25 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.

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

African (AFR) AF: 0.000104 AC: 3 AN: 28812

American (AMR) AF: 0.00273 AC: 27 AN: 9880

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3158

East Asian (EAS) AF: 0.00253 AC: 8 AN: 3156

South Asian (SAS) AF: 0.000363 AC: 1 AN: 2756

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6170

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 194

European-Non Finnish (NFE) AF: 0.000147 AC: 8 AN: 54428

Other (OTH) AF: 0.000670 AC: 1 AN: 1492

Alfa AF: 0.00102 Hom.: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs375025208; hg19: chr7-73254451; COSMIC: COSV52895030;