18-32208211-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005925.3(MEP1B):c.859C>T(p.Arg287Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 1,613,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: MEP1B NM_005925.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.573

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]

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]

ACMG classification

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=0.11331403).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEP1B	NM_005925.3	c.859C>T	p.Arg287Trp	missense_variant	9/15	ENST00000269202.11
MEP1B	NM_001308171.2	c.859C>T	p.Arg287Trp	missense_variant	9/15
MEP1B	XM_011526013.3	c.640C>T	p.Arg214Trp	missense_variant	8/14
MEP1B	XM_011526014.3	c.548-2290C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEP1B	ENST00000269202.11	c.859C>T	p.Arg287Trp	missense_variant	9/15	1	NM_005925.3	P4
MEP1B	ENST00000581447.1	c.859C>T	p.Arg287Trp	missense_variant	9/15	1		A1
GAREM1	ENST00000583696.1	c.66-71751G>A		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152126 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.0000241 AC: 6 AN: 249252 Hom.: 0 AF XY: 0.0000296 AC XY: 4 AN XY: 135222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000167

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.0000253 AC: 37 AN: 1461676 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 727128

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000190 AC: 29 AN: 152244 Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74430

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.000431

ExAC AF: 0.0000248 AC: 3

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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

Jul 15, 2021

The c.859C>T (p.R287W) alteration is located in exon 9 (coding exon 9) of the MEP1B gene. This alteration results from a C to T substitution at nucleotide position 859, causing the arginine (R) at amino acid position 287 to be replaced by a tryptophan (W). 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	0.068
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Benign	0.33	T;T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.34	N
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.8	M;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-4.1	D;.
REVEL	Benign	0.061
Sift	Benign	0.045	D;.
Sift4G	Uncertain	0.051	T;T
Polyphen		0.40	B;.
Vest4		0.28
MutPred		0.64		Gain of sheet (P = 0.0149);Gain of sheet (P = 0.0149);
MVP		0.41
MPC		0.19
ClinPred		0.86	D
GERP RS		1.2
Varity_R		0.66
gMVP		0.84

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

Other links and lift over

dbSNP: rs201959687; hg19: chr18-29788174;