Variant 1-2592689-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP3BP4_ModerateBP6_Very_StrongBS2

The NM_033467.4(MMEL1):c.2033T>C(p.Ile678Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00309 in 1,604,972 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0025 ( 0 hom., cov: 25)

Exomes 𝑓: 0.0031 ( 16 hom. )

Consequence

MMEL1
NM_033467.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 6.08

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, BayesDel_noAF, Cadd, M_CAP, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.11245319).

BP6

Variant 1-2592689-A-G is Benign according to our data. Variant chr1-2592689-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 708734.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMEL1	NM_033467.4 linkuse as main transcript	c.2033T>C	p.Ile678Thr	missense_variant	21/24	ENST00000378412.8	NP_258428.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMEL1	ENST00000378412.8 linkuse as main transcript	c.2033T>C	p.Ile678Thr	missense_variant	21/24	2	NM_033467.4	ENSP00000367668	P1	Q495T6-1

Frequencies

GnomAD3 genomes

AF:

0.00248

AC:

365

AN:

147428

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000836

Gnomad AMI

AF:

0.00223

Gnomad AMR

AF:

0.00263

Gnomad ASJ

AF:

0.000582

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00130

Gnomad FIN

AF:

0.00373

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00349

Gnomad OTH

AF:

0.00593

GnomAD3 exomes

AF:

0.00281

AC:

701

AN:

249116

Hom.:

AF XY:

0.00286

AC XY:

386

AN XY:

135002

show subpopulations

Gnomad AFR exome

AF:

0.000433

Gnomad AMR exome

AF:

0.00218

Gnomad ASJ exome

AF:

0.000709

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00246

Gnomad FIN exome

AF:

0.00438

Gnomad NFE exome

AF:

0.00380

Gnomad OTH exome

AF:

0.00280

GnomAD4 exome

AF:

0.00315

AC:

4587

AN:

1457430

Hom.:

Cov.:

AF XY:

0.00319

AC XY:

2314

AN XY:

725078

show subpopulations

Gnomad4 AFR exome

AF:

0.000270

Gnomad4 AMR exome

AF:

0.00222

Gnomad4 ASJ exome

AF:

0.000849

Gnomad4 EAS exome

AF:

0.0000254

Gnomad4 SAS exome

AF:

0.00253

Gnomad4 FIN exome

AF:

0.00436

Gnomad4 NFE exome

AF:

0.00342

Gnomad4 OTH exome

AF:

0.00331

GnomAD4 genome

AF:

0.00248

AC:

366

AN:

147542

Hom.:

Cov.:

AF XY:

0.00268

AC XY:

193

AN XY:

71910

show subpopulations

Gnomad4 AFR

AF:

0.000834

Gnomad4 AMR

AF:

0.00263

Gnomad4 ASJ

AF:

0.000582

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00152

Gnomad4 FIN

AF:

0.00373

Gnomad4 NFE

AF:

0.00349

Gnomad4 OTH

AF:

0.00587

Alfa

AF:

0.00315

Hom.:

Bravo

AF:

0.00278

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00302

AC:

ExAC

AF:

0.00313

AC:

380

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 25, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Uncertain

0.087

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

D;.

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.53

MetaRNN

Benign

0.11

T;T

MetaSVM

Uncertain

0.79

MutationAssessor

Uncertain

2.3

M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-4.8

D;D

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.98

MVP

0.76

MPC

0.80

ClinPred

0.036

GERP RS

4.3

Varity_R

0.79

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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