chr7-73840034-G-T

Position:

• chr7-73840034-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_152559.3(METTL27):​c.475C>A​(p.Pro159Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: METTL27 NM_152559.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.99

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.865

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
METTL27	NM_152559.3	c.475C>A	p.Pro159Thr	missense_variant	5/6	ENST00000297873.9	NP_689772.2
METTL27	XM_017011777.2	c.475C>A	p.Pro159Thr	missense_variant	5/6		XP_016867266.1
METTL27	XM_017011778.2	c.475C>A	p.Pro159Thr	missense_variant	5/6		XP_016867267.1
METTL27	XR_001744563.2	n.506C>A		non_coding_transcript_exon_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
METTL27	ENST00000297873.9	c.475C>A	p.Pro159Thr	missense_variant	5/6	1	NM_152559.3	ENSP00000297873.4
METTL27	ENST00000458679.5	n.*66C>A		non_coding_transcript_exon_variant	4/5	4		ENSP00000398533.1
METTL27	ENST00000493174.1	n.370C>A		non_coding_transcript_exon_variant	4/4	2
METTL27	ENST00000458679.5	n.*66C>A		3_prime_UTR_variant	4/5	4		ENSP00000398533.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2022

The c.475C>A (p.P159T) alteration is located in exon 5 (coding exon 4) of the WBSCR27 gene. This alteration results from a C to A substitution at nucleotide position 475, causing the proline (P) at amino acid position 159 to be replaced by a threonine (T). 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	0.12
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.47	D
PrimateAI	Uncertain	0.48	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.60
MutPred		0.83		Loss of methylation at K158 (P = 0.1568);
MVP		0.72
MPC		0.60
ClinPred		0.99	D
GERP RS		3.5
Varity_R		0.47
gMVP		0.56

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-73254364;