18-32210654-A-C

Position:

• chr18-32210654-A-C

Variant summary

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

The NM_005925.3(MEP1B):​c.1073A>C​(p.Tyr358Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000376 in 1,461,658 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: MEP1B NM_005925.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.23

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEP1B	NM_005925.3	c.1073A>C	p.Tyr358Ser	missense_variant	10/15	ENST00000269202.11	NP_005916.2
MEP1B	NM_001308171.2	c.1073A>C	p.Tyr358Ser	missense_variant	10/15		NP_001295100.1
MEP1B	XM_011526013.3	c.854A>C	p.Tyr285Ser	missense_variant	9/14		XP_011524315.1
MEP1B	XM_011526014.3	c.701A>C	p.Tyr234Ser	missense_variant	8/13		XP_011524316.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEP1B	ENST00000269202.11	c.1073A>C	p.Tyr358Ser	missense_variant	10/15	1	NM_005925.3	ENSP00000269202.6
MEP1B	ENST00000581447.1	c.1073A>C	p.Tyr358Ser	missense_variant	10/15	1		ENSP00000463280.1
GAREM1	ENST00000583696.1	c.64-74194T>G		intron_variant		3		ENSP00000464185.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000201 AC: 5 AN: 249224 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135200

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

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: 0.0000177

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000376 AC: 55 AN: 1461658 Hom.: 0 Cov.: 31 AF XY: 0.0000371 AC XY: 27 AN XY: 727110

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000450

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 33

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000248 AC: 3

EpiCase AF: 0.000109

EpiControl AF: 0.000119

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 29, 2024

The c.1073A>C (p.Y358S) alteration is located in exon 10 (coding exon 10) of the MEP1B gene. This alteration results from a A to C substitution at nucleotide position 1073, causing the tyrosine (Y) at amino acid position 358 to be replaced by a serine (S). 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	0.13
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.28	T;T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.72	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.1	M;.
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-5.7	D;.
REVEL	Benign	0.21
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.017	D;D
Polyphen		0.96	D;.
Vest4		0.61
MutPred		0.70		Gain of disorder (P = 0.0066);Gain of disorder (P = 0.0066);
MVP		0.39
MPC		0.56
ClinPred		0.84	D
GERP RS		3.0
Varity_R		0.75
gMVP		0.83

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

Other links and lift over

dbSNP: rs755962966; hg19: chr18-29790617;