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GeneBe

5-41000344-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_173489.5(MROH2B):c.4358G>A(p.Arg1453His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,613,202 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

MROH2B
NM_173489.5 missense

Scores

1
6
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.47
Variant links:
Genes affected
MROH2B (HGNC:26857): (maestro heat like repeat family member 2B) Predicted to be involved in protein kinase A signaling. Predicted to be located in acrosomal vesicle and sperm midpiece. [provided by Alliance of Genome Resources, Apr 2022]
C7 (HGNC:1346): (complement C7) This gene encodes a serum glycoprotein that forms a membrane attack complex together with complement components C5b, C6, C8, and C9 as part of the terminal complement pathway of the innate immune system. The protein encoded by this gene contains a cholesterol-dependent cytolysin/membrane attack complex/perforin-like (CDC/MACPF) domain and belongs to a large family of structurally related molecules that form pores involved in host immunity and bacterial pathogenesis. This protein initiates membrane attack complex formation by binding the C5b-C6 subcomplex and inserts into the phospholipid bilayer, serving as a membrane anchor. Mutations in this gene are associated with a rare disorder called C7 deficiency. [provided by RefSeq, Nov 2016]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.32455748).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MROH2BNM_173489.5 linkuse as main transcriptc.4358G>A p.Arg1453His missense_variant 39/42 ENST00000399564.5
MROH2BXM_011513952.2 linkuse as main transcriptc.4358G>A p.Arg1453His missense_variant 39/43
MROH2BXM_011513953.2 linkuse as main transcriptc.4172G>A p.Arg1391His missense_variant 38/41

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MROH2BENST00000399564.5 linkuse as main transcriptc.4358G>A p.Arg1453His missense_variant 39/421 NM_173489.5 P1Q7Z745-1

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152152
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000243
AC:
6
AN:
247416
Hom.:
0
AF XY:
0.0000224
AC XY:
3
AN XY:
134212
show subpopulations
Gnomad AFR exome
AF:
0.000194
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000558
Gnomad SAS exome
AF:
0.0000329
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000893
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000192
AC:
28
AN:
1461050
Hom.:
0
Cov.:
35
AF XY:
0.0000234
AC XY:
17
AN XY:
726794
show subpopulations
Gnomad4 AFR exome
AF:
0.000150
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000162
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152152
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74324
show subpopulations
Gnomad4 AFR
AF:
0.000121
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000763
Hom.:
0
Bravo
AF:
0.0000756
ESP6500AA
AF:
0.000522
AC:
2
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000248
AC:
3
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000594

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 28, 2022The c.4358G>A (p.R1453H) alteration is located in exon 39 (coding exon 39) of the MROH2B gene. This alteration results from a G to A substitution at nucleotide position 4358, causing the arginine (R) at amino acid position 1453 to be replaced by a histidine (H). 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
0.16
BayesDel_addAF
Benign
-0.19
T
BayesDel_noAF
Benign
-0.24
Cadd
Uncertain
25
Dann
Pathogenic
1.0
DEOGEN2
Benign
0.17
T;T
Eigen
Uncertain
0.63
Eigen_PC
Uncertain
0.65
FATHMM_MKL
Uncertain
0.83
D
LIST_S2
Benign
0.83
T;T
M_CAP
Benign
0.022
T
MetaRNN
Benign
0.32
T;T
MetaSVM
Benign
-0.37
T
MutationTaster
Benign
0.98
D;D
PrimateAI
Benign
0.35
T
PROVEAN
Uncertain
-2.4
N;N
REVEL
Uncertain
0.34
Sift
Benign
0.031
D;T
Sift4G
Uncertain
0.032
D;D
Polyphen
0.99
.;D
Vest4
0.32
MVP
0.49
MPC
0.16
ClinPred
0.45
T
GERP RS
6.0
Varity_R
0.10
gMVP
0.39

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
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.

Other links and lift over

dbSNP: rs367639574; hg19: chr5-41000446; COSMIC: COSV68180867; COSMIC: COSV68180867; API