chr16-635676-G-T

Position:

• chr16-635676-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032366.5(METTL26):​c.296C>A​(p.Pro99Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000142 in 1,403,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: METTL26 NM_032366.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.75

Genes affected

METTL26 (HGNC:14141): (methyltransferase like 26)

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3633613).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
METTL26	NM_032366.5	c.296C>A	p.Pro99Gln	missense_variant	2/6	ENST00000301686.13	NP_115742.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
METTL26	ENST00000301686.13	c.296C>A	p.Pro99Gln	missense_variant	2/6	2	NM_032366.5	ENSP00000445926	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1403666 Hom.: 0 Cov.: 32 AF XY: 0.00000144 AC XY: 1 AN XY: 692904

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000185

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Oct 06, 2021

The c.296C>A (p.P99Q) alteration is located in exon 2 (coding exon 2) of the METTL26 gene. This alteration results from a C to A substitution at nucleotide position 296, causing the proline (P) at amino acid position 99 to be replaced by a glutamine (Q). 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	0.23
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.032	T;.;T;.;.;.
Eigen	Benign	-0.030
Eigen_PC	Benign	-0.024
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.80	T;T;T;T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.36	T;T;T;T;T;T
MetaSVM	Benign	-0.87	T
MutationTaster	Benign	1.0	D;D;D;D;D
PROVEAN	Uncertain	-2.5	.;D;D;D;D;D
REVEL	Benign	0.11
Sift	Benign	0.082	.;T;T;T;D;T
Sift4G	Benign	0.32	T;D;T;D;.;D
Polyphen		0.47	.;.;P;.;.;.
Vest4		0.26
MutPred		0.55		Gain of helix (P = 0.0082);Gain of helix (P = 0.0082);Gain of helix (P = 0.0082);Gain of helix (P = 0.0082);.;Gain of helix (P = 0.0082);
MVP		0.42
MPC		0.034
ClinPred		0.82	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs1213022009; hg19: chr16-685676;