Variant chr7-73840513-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_152559.3(METTL27):c.289G>C(p.Asp97His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000309 in 1,457,382 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

METTL27
NM_152559.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.06

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:

METTL27 (HGNC:):

METTL27 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.972

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
METTL27	NM_152559.3 linkuse as main transcript	c.289G>C	p.Asp97His	missense_variant	4/6	ENST00000297873.9	NP_689772.2	Q8N6F8
METTL27	XM_017011777.2 linkuse as main transcript	c.289G>C	p.Asp97His	missense_variant	4/6		XP_016867266.1
METTL27	XM_017011778.2 linkuse as main transcript	c.289G>C	p.Asp97His	missense_variant	4/6		XP_016867267.1
METTL27	XR_001744563.2 linkuse as main transcript	n.320G>C		non_coding_transcript_exon_variant	4/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
METTL27	ENST00000297873.9 linkuse as main transcript	c.289G>C	p.Asp97His	missense_variant	4/6	1	NM_152559.3	ENSP00000297873.4	Q8N6F8
METTL27	ENST00000458679.5 linkuse as main transcript	n.253-393G>C		intron_variant		4		ENSP00000398533.1	B4DWM3
METTL27	ENST00000493174.1 linkuse as main transcript	n.284-393G>C		intron_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000781

AC:

AN:

243242

Hom.:

AF XY:

0.000128

AC XY:

AN XY:

132838

show subpopulations

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 SAS exome

AF:

0.000627

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000309

AC:

AN:

1457382

Hom.:

Cov.:

AF XY:

0.0000497

AC XY:

AN XY:

724900

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000489

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000333

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 01, 2024

The c.289G>C (p.D97H) alteration is located in exon 4 (coding exon 3) of the WBSCR27 gene. This alteration results from a G to C substitution at nucleotide position 289, causing the aspartic acid (D) at amino acid position 97 to be replaced by a histidine (H). 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

Uncertain

0.53

BayesDel_addAF

Benign

-0.026

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.37

Eigen

Benign

0.18

Eigen_PC

Benign

-0.027

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.87

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

0.91

PrimateAI

Uncertain

0.52

PROVEAN

Pathogenic

-6.2

REVEL

Pathogenic

0.71

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.75

MutPred

0.94

Gain of disorder (P = 0.2025);

MVP

0.78

MPC

0.62

ClinPred

0.94

GERP RS

3.6

Varity_R

0.94

gMVP

0.89

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over