rs150434290
Positions:
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting
The NM_001038603.3(MARVELD2):c.176C>T(p.Pro59Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000966 in 1,614,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00050 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0010 ( 0 hom. )
Consequence
MARVELD2
NM_001038603.3 missense
NM_001038603.3 missense
Scores
1
6
6
Clinical Significance
Conservation
PhyloP100: 4.43
Genes affected
MARVELD2 (HGNC:26401): (MARVEL domain containing 2) The protein encoded by this gene is a membrane protein found at the tight junctions between epithelial cells. The encoded protein helps establish epithelial barriers such as those in the organ of Corti, where these barriers are required for normal hearing. Defects in this gene are a cause of deafness autosomal recessive type 49 (DFNB49). Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -1 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.07942179).
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000499 (76/152298) while in subpopulation NFE AF= 0.000853 (58/68030). AF 95% confidence interval is 0.000677. There are 0 homozygotes in gnomad4. There are 26 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MARVELD2 | NM_001038603.3 | c.176C>T | p.Pro59Leu | missense_variant | 2/7 | ENST00000325631.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MARVELD2 | ENST00000325631.10 | c.176C>T | p.Pro59Leu | missense_variant | 2/7 | 1 | NM_001038603.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000499 AC: 76AN: 152180Hom.: 0 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
76
AN:
152180
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.000501 AC: 126AN: 251354Hom.: 0 AF XY: 0.000552 AC XY: 75AN XY: 135852
GnomAD3 exomes
AF:
AC:
126
AN:
251354
Hom.:
AF XY:
AC XY:
75
AN XY:
135852
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00101 AC: 1483AN: 1461848Hom.: 0 Cov.: 35 AF XY: 0.000982 AC XY: 714AN XY: 727220
GnomAD4 exome
AF:
AC:
1483
AN:
1461848
Hom.:
Cov.:
35
AF XY:
AC XY:
714
AN XY:
727220
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.000499 AC: 76AN: 152298Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26AN XY: 74468
GnomAD4 genome
?
AF:
AC:
76
AN:
152298
Hom.:
Cov.:
32
AF XY:
AC XY:
26
AN XY:
74468
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
TwinsUK
AF:
AC:
5
ALSPAC
AF:
AC:
5
ESP6500AA
AF:
AC:
2
ESP6500EA
AF:
AC:
5
ExAC
?
AF:
AC:
58
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 16, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 10, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 20, 2022 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 59 of the MARVELD2 protein (p.Pro59Leu). This variant is present in population databases (rs150434290, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with MARVELD2-related conditions. ClinVar contains an entry for this variant (Variation ID: 287288). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 21, 2016 | The p.Pro59Leu variant in MARVELD2 has not been previously reported in individua ls with hearing loss, but it has been identified in 0.1% (51/66680) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs150434290). Although this variant has been seen in the general po pulation, its frequency is not high enough to rule out a pathogenic role. Comput ational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Pro59Leu variant is uncertain. - |
Autosomal recessive nonsyndromic hearing loss 49 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;M;M;M;.;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
Polyphen
D;D;D;D;D;.;.;.
Vest4
0.56, 0.56, 0.56
MVP
0.80
MPC
0.10
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at