7-73840108-G-A

Variant names:

• chr7-73840108-G-A
• rs980702144
• NM_152559.3:c.401C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152559.3(METTL27):​c.401C>T​(p.Ala134Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000024 in 1,584,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A134T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: METTL27 NM_152559.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.83
• Publications: 1 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2607962).

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.401C>T	p.Ala134Val	missense	Exon 5 of 6	NP_689772.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	METTL27	ENST00000297873.9	TSL:1 MANE Select	c.401C>T	p.Ala134Val	missense	Exon 5 of 6	ENSP00000297873.4	Q8N6F8
	METTL27	ENST00000866837.1		c.401C>T	p.Ala134Val	missense	Exon 5 of 6	ENSP00000536896.1
	METTL27	ENST00000866839.1		c.401C>T	p.Ala134Val	missense	Exon 5 of 6	ENSP00000536898.1

Frequencies

GnomAD3 genomes AF: 0.0000135 AC: 2 AN: 148218 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000249

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: 0.0000149

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000816 AC: 2 AN: 245000 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000180

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000251 AC: 36 AN: 1436776 Hom.: 0 Cov.: 34 AF XY: 0.0000266 AC XY: 19 AN XY: 714518

African (AFR) AF: 0.0000306 AC: 1 AN: 32708

American (AMR) AF: 0.00 AC: 0 AN: 43636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25594

East Asian (EAS) AF: 0.00 AC: 0 AN: 36452

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 85056

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50688

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.0000310 AC: 34 AN: 1098172

Other (OTH) AF: 0.00 AC: 0 AN: 58772

GnomAD4 genome AF: 0.0000135 AC: 2 AN: 148218 Hom.: 0 Cov.: 30 AF XY: 0.0000277 AC XY: 2 AN XY: 72242

African (AFR) AF: 0.0000249 AC: 1 AN: 40158

American (AMR) AF: 0.00 AC: 0 AN: 14908

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3444

East Asian (EAS) AF: 0.00 AC: 0 AN: 4850

South Asian (SAS) AF: 0.00 AC: 0 AN: 4358

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10198

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000149 AC: 1 AN: 67058

Other (OTH) AF: 0.00 AC: 0 AN: 2034

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	12
DANN	Benign	0.54
DEOGEN2	Benign	0.0091	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.1	T
PhyloP100		2.8
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.17
Sift	Benign	0.31	T
Sift4G	Benign	1.0	T
Polyphen		0.85	P
Vest4		0.32
MutPred		0.46		Loss of glycosylation at T131 (P = 0.1659)
MVP		0.088
MPC		0.21
ClinPred		0.14	T
GERP RS		3.8
Varity_R		0.11
gMVP		0.51
Mutation Taster		=92/8	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: rs980702144; hg19: chr7-73254438; COSMIC: COSV52897739;