Variant 1-2591042-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_033467.4(MMEL1):c.2288A>G(p.His763Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,454,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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

MMEL1
NM_033467.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.90

Variant links:

Genes affected

MMEL1 (HGNC:14668): (membrane metalloendopeptidase like 1) The protein encoded by this gene is a member of the neutral endopeptidase (NEP) or membrane metallo-endopeptidase (MME) family. Family members play important roles in pain perception, arterial pressure regulation, phosphate metabolism and homeostasis. This protein is a type II transmembrane protein and is thought to be expressed as a secreted protein. This gene is expressed mainly in testis with weak expression in the brain, kidney, and heart. [provided by RefSeq, Jul 2008]

MMEL1 links:

PRXL2B (HGNC:28390): (peroxiredoxin like 2B) Predicted to enable antioxidant activity and prostaglandin-F synthase activity. Predicted to be involved in prostaglandin biosynthetic process. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

PRXL2B links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2420257).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMEL1	NM_033467.4 linkuse as main transcript	c.2288A>G	p.His763Arg	missense_variant	24/24	ENST00000378412.8	NP_258428.2
PRXL2B	NM_152371.5 linkuse as main transcript	c.*1615T>C		3_prime_UTR_variant	7/7	ENST00000419916.8	NP_689584.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMEL1	ENST00000378412.8 linkuse as main transcript	c.2288A>G	p.His763Arg	missense_variant	24/24	2	NM_033467.4	ENSP00000367668	P1	Q495T6-1
PRXL2B	ENST00000419916.8 linkuse as main transcript	c.*1615T>C		3_prime_UTR_variant	7/7	1	NM_152371.5	ENSP00000394405	P1	Q8TBF2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000421

AC:

AN:

237534

Hom.:

AF XY:

0.00

AC XY:

AN XY:

129044

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000299

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1454238

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

722830

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000456

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000936

Hom.:

Bravo

AF:

0.00000378

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 17, 2022

The c.2288A>G (p.H763R) alteration is located in exon 24 (coding exon 23) of the MMEL1 gene. This alteration results from a A to G substitution at nucleotide position 2288, causing the histidine (H) at amino acid position 763 to be replaced by an arginine (R). 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

0.057

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Benign

0.50

DEOGEN2

Uncertain

0.57

.;D;.

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.76

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.74

T;T;T

M_CAP

Uncertain

0.099

MetaRNN

Benign

0.24

T;T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.3

.;L;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.8

.;N;N

REVEL

Benign

0.16

Sift

Benign

0.13

.;T;T

Sift4G

Benign

0.072

T;T;T

Polyphen

0.0010

.;B;.

Vest4

0.20, 0.28

MutPred

0.47

.;Loss of methylation at R766 (P = 0.0673);.;

MVP

0.39

MPC

0.21

ClinPred

0.047

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.044

gMVP

0.28

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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