7-73840121-CTGTG-C

Variant names:

• chr7-73840121-CTGTG-C
• rs375025208
• NM_152559.3:c.389-5_389-2delCACA

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.389-5_389-2delCACA 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 0.000615 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 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 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 rank	MANE	Protein	UniProt
METTL27	NM_152559.3	c.389-5_389-2delCACA		splice_acceptor_variant, splice_region_variant, intron_variant	Intron 4 of 5	ENST00000297873.9	NP_689772.2
METTL27	XM_017011777.2	c.389-5_389-2delCACA		splice_acceptor_variant, splice_region_variant, intron_variant	Intron 4 of 5		XP_016867266.1
METTL27	XM_017011778.2	c.389-5_389-2delCACA		splice_acceptor_variant, splice_region_variant, intron_variant	Intron 4 of 5		XP_016867267.1
METTL27	XR_001744563.2	n.420-5_420-2delCACA		splice_acceptor_variant, splice_region_variant, intron_variant	Intron 4 of 6

Ensembl

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

GnomAD2 exomes AF: 0.00308 AC: 652 AN: 211532 AF XY: 0.00311

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 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

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

African (AFR) AF: 0.000296 AC: 9 AN: 30398

American (AMR) AF: 0.00124 AC: 48 AN: 38642

Ashkenazi Jewish (ASJ) AF: 0.000125 AC: 3 AN: 23948

East Asian (EAS) AF: 0.00171 AC: 62 AN: 36194

South Asian (SAS) AF: 0.00242 AC: 186 AN: 76914

European-Finnish (FIN) AF: 0.000822 AC: 39 AN: 47426

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5456

European-Non Finnish (NFE) AF: 0.000506 AC: 524 AN: 1035036

Other (OTH) AF: 0.000470 AC: 26 AN: 55320

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

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

African (AFR) AF: 0.00 AC: 0 AN: 28734

American (AMR) AF: 0.00 AC: 0 AN: 9872

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3160

South Asian (SAS) AF: 0.00 AC: 0 AN: 2760

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 210

European-Non Finnish (NFE) AF: 0.0000184 AC: 1 AN: 54432

Other (OTH) AF: 0.00 AC: 0 AN: 1496

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000340 Hom.: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1
Mutation Taster		=94/6	polymorphism (auto)

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: COSV52895434;