Genetic Variant NM_173489.5:c.3536T>C (chr5-41008678-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_173489.5(MROH2B):c.3536T>C(p.Leu1179Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.819 in 1,613,692 control chromosomes in the GnomAD database, including 542,025 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.83 ( 52263 hom., cov: 32)

Exomes 𝑓: 0.82 ( 489762 hom. )

Consequence

MROH2B
NM_173489.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.82

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]

MROH2B links:

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]

C7 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.4985399E-6).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.866 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
MROH2B	NM_173489.5 link	c.3536T>C	p.Leu1179Pro	missense_variant	Exon 33 of 42	ENST00000399564.5	NP_775760.3
MROH2B	XM_011513952.2 link	c.3536T>C	p.Leu1179Pro	missense_variant	Exon 33 of 43		XP_011512254.1
MROH2B	XM_011513953.2 link	c.3350T>C	p.Leu1117Pro	missense_variant	Exon 32 of 41		XP_011512255.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MROH2B	ENST00000399564.5 link	c.3536T>C	p.Leu1179Pro	missense_variant	Exon 33 of 42	1	NM_173489.5	ENSP00000382476.4		Q7Z745-1

Frequencies

GnomAD3 genomes

AF:

0.827

AC:

125691

AN:

152016

Hom.:

52216

Cov.:

show subpopulations

Gnomad AFR

AF:

0.874

Gnomad AMI

AF:

0.685

Gnomad AMR

AF:

0.862

Gnomad ASJ

AF:

0.797

Gnomad EAS

AF:

0.632

Gnomad SAS

AF:

0.786

Gnomad FIN

AF:

0.765

Gnomad MID

AF:

0.759

Gnomad NFE

AF:

0.822

Gnomad OTH

AF:

0.827

GnomAD3 exomes

AF:

0.804

AC:

199930

AN:

248692

Hom.:

80981

AF XY:

0.804

AC XY:

108419

AN XY:

134902

show subpopulations

Gnomad AFR exome

AF:

0.875

Gnomad AMR exome

AF:

0.844

Gnomad ASJ exome

AF:

0.789

Gnomad EAS exome

AF:

0.618

Gnomad SAS exome

AF:

0.798

Gnomad FIN exome

AF:

0.776

Gnomad NFE exome

AF:

0.819

Gnomad OTH exome

AF:

0.807

GnomAD4 exome

AF:

0.818

AC:

1195019

AN:

1461558

Hom.:

489762

Cov.:

AF XY:

0.817

AC XY:

593956

AN XY:

727048

show subpopulations

Gnomad4 AFR exome

AF:

0.880

Gnomad4 AMR exome

AF:

0.845

Gnomad4 ASJ exome

AF:

0.788

Gnomad4 EAS exome

AF:

0.657

Gnomad4 SAS exome

AF:

0.803

Gnomad4 FIN exome

AF:

0.773

Gnomad4 NFE exome

AF:

0.825

Gnomad4 OTH exome

AF:

0.806

GnomAD4 genome

AF:

0.827

AC:

125797

AN:

152134

Hom.:

52263

Cov.:

AF XY:

0.824

AC XY:

61297

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.874

Gnomad4 AMR

AF:

0.862

Gnomad4 ASJ

AF:

0.797

Gnomad4 EAS

AF:

0.632

Gnomad4 SAS

AF:

0.787

Gnomad4 FIN

AF:

0.765

Gnomad4 NFE

AF:

0.822

Gnomad4 OTH

AF:

0.822

Alfa

AF:

0.820

Hom.:

132099

Bravo

AF:

0.833

TwinsUK

AF:

0.828

AC:

3071

ALSPAC

AF:

0.826

AC:

3185

ESP6500AA

AF:

0.881

AC:

3635

ESP6500EA

AF:

0.818

AC:

6876

ExAC

AF:

0.802

AC:

96986

Asia WGS

AF:

0.687

AC:

2390

AN:

3478

EpiCase

AF:

0.831

EpiControl

AF:

0.830

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.035

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.66

CADD

Benign

DANN

Benign

0.067

DEOGEN2

Benign

0.0033

T;T

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.22

T;T

MetaRNN

Benign

0.0000015

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-2.7

.;N

PrimateAI

Benign

0.40

PROVEAN

Benign

5.2

N;N

REVEL

Benign

0.065

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

.;B

Vest4

0.047

MPC

0.024

ClinPred

0.0051

GERP RS

4.2

Varity_R

0.039

gMVP

0.076

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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