dbSNP rs752399620: MEP1B:p.Ile140Leu (chr18-32204231-A-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005925.3(MEP1B):c.418A>C(p.Ile140Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,292 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I140F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

MEP1B
NM_005925.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.28

Variant links:

Genes affected

MEP1B (HGNC:7020): (meprin A subunit beta) Meprins are multidomain zinc metalloproteases that are highly expressed in mammalian kidney and intestinal brush border membranes, and in leukocytes and certain cancer cells. They are involved in the hydrolysis of a variety of peptide and protein substrates, and have been implicated in cancer and intestinal inflammation. Mature meprins are oligomers of evolutionarily related, but separately encoded alpha and/or beta subunits. Homooligomers of alpha subunit are secreted, whereas, oligomers containing the beta subunit are plasma membrane-bound. This gene encodes the beta subunit. Targeted disruption of this gene in mice affects embryonic viability, renal gene expression profiles, and distribution of the membrane-associated alpha subunit in kidney and intestine. [provided by RefSeq, Oct 2011]

MEP1B links:

GAREM1 (HGNC:26136): (GRB2 associated regulator of MAPK1 subtype 1) This gene encodes an adaptor protein which functions in the epidermal growth factor (EGF) receptor-mediated signaling pathway. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

GAREM1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEP1B	NM_005925.3 link	c.418A>C	p.Ile140Leu	missense_variant	Exon 7 of 15	ENST00000269202.11	NP_005916.2	Q16820
MEP1B	NM_001308171.2 link	c.418A>C	p.Ile140Leu	missense_variant	Exon 7 of 15		NP_001295100.1	Q16820J3QKX5
MEP1B	XM_011526013.3 link	c.418A>C	p.Ile140Leu	missense_variant	Exon 7 of 14		XP_011524315.1
MEP1B	XM_011526014.3 link	c.418A>C	p.Ile140Leu	missense_variant	Exon 7 of 13		XP_011524316.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MEP1B	ENST00000269202.11 link	c.418A>C	p.Ile140Leu	missense_variant	Exon 7 of 15	1	NM_005925.3	ENSP00000269202.6	Q16820
MEP1B	ENST00000581447.1 link	c.418A>C	p.Ile140Leu	missense_variant	Exon 7 of 15	1		ENSP00000463280.1	J3QKX5
GAREM1	ENST00000583696.1 link	c.64-67771T>G		intron_variant	Intron 1 of 2	3		ENSP00000464185.1	J3QRF3
MEP1B	ENST00000581184.5 link	n.463A>C		non_coding_transcript_exon_variant	Exon 7 of 7	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000423

AC:

AN:

236498

Hom.:

AF XY:

0.00000783

AC XY:

AN XY:

127764

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000933

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1454292

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

722456

show subpopulations

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:

9.02e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.047

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

T;T;T

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.83

T;D;D

M_CAP

Benign

0.011

MetaRNN

Uncertain

0.48

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.16

.;N;.

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.6

.;N;.

REVEL

Benign

0.16

Sift

Benign

0.094

.;T;.

Sift4G

Benign

1.0

T;T;T

Polyphen

0.37

.;B;.

Vest4

0.66, 0.59

MutPred

0.56

.;Loss of methylation at K135 (P = 0.0898);Loss of methylation at K135 (P = 0.0898);

MVP

0.55

MPC

0.26

ClinPred

0.80

GERP RS

5.9

Varity_R

0.46

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over