7-73840416-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_152559.3(METTL27):ā€‹c.386A>Cā€‹(p.Glu129Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000508 in 1,573,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 31)
Exomes š‘“: 0.0000042 ( 0 hom. )

Consequence

METTL27
NM_152559.3 missense, splice_region

Scores

18
Splicing: ADA: 0.00009638
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.08
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.038269848).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
METTL27NM_152559.3 linkc.386A>C p.Glu129Ala missense_variant, splice_region_variant Exon 4 of 6 ENST00000297873.9 NP_689772.2 Q8N6F8
METTL27XM_017011777.2 linkc.386A>C p.Glu129Ala missense_variant, splice_region_variant Exon 4 of 6 XP_016867266.1
METTL27XM_017011778.2 linkc.386A>C p.Glu129Ala missense_variant, splice_region_variant Exon 4 of 6 XP_016867267.1
METTL27XR_001744563.2 linkn.417A>C splice_region_variant, non_coding_transcript_exon_variant Exon 4 of 7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
METTL27ENST00000297873.9 linkc.386A>C p.Glu129Ala missense_variant, splice_region_variant Exon 4 of 6 1 NM_152559.3 ENSP00000297873.4 Q8N6F8
METTL27ENST00000458679.5 linkn.253-296A>C intron_variant Intron 3 of 4 4 ENSP00000398533.1 B4DWM3
METTL27ENST00000493174.1 linkn.284-296A>C intron_variant Intron 3 of 3 2

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
151966
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000164
AC:
3
AN:
183412
Hom.:
0
AF XY:
0.0000303
AC XY:
3
AN XY:
99078
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000360
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000422
AC:
6
AN:
1421748
Hom.:
0
Cov.:
31
AF XY:
0.00000426
AC XY:
3
AN XY:
703760
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000259
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000275
Gnomad4 OTH exome
AF:
0.0000339
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
152082
Hom.:
0
Cov.:
31
AF XY:
0.0000134
AC XY:
1
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Sep 30, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.386A>C (p.E129A) alteration is located in exon 4 (coding exon 3) of the WBSCR27 gene. This alteration results from a A to C substitution at nucleotide position 386, causing the glutamic acid (E) at amino acid position 129 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.080
BayesDel_addAF
Benign
-0.18
T
BayesDel_noAF
Benign
-0.44
CADD
Benign
13
DANN
Benign
0.56
DEOGEN2
Benign
0.0080
T
Eigen
Benign
-0.74
Eigen_PC
Benign
-0.67
FATHMM_MKL
Benign
0.10
N
LIST_S2
Benign
0.72
T
M_CAP
Benign
0.015
T
MetaRNN
Benign
0.038
T
MetaSVM
Benign
-1.0
T
PrimateAI
Benign
0.35
T
PROVEAN
Benign
-0.75
N
REVEL
Benign
0.10
Sift
Benign
0.57
T
Sift4G
Benign
0.51
T
Polyphen
0.015
B
Vest4
0.12
MVP
0.23
MPC
0.14
ClinPred
0.019
T
GERP RS
2.2
Varity_R
0.13
gMVP
0.46

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000096
dbscSNV1_RF
Benign
0.016
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs182367694; hg19: chr7-73254746; API