dbSNP rs200489389: MROH2B:p.Ser1522Ile (chr5-40999697-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_173489.5(MROH2B):c.4565G>T(p.Ser1522Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,820 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: 6.8e-7 ( 0 hom. )

Consequence

MROH2B
NM_173489.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.48

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein
MROH2B	NM_173489.5 link	c.4565G>T	p.Ser1522Ile	missense_variant	Exon 40 of 42	ENST00000399564.5	NP_775760.3
MROH2B	XM_011513952.2 link	c.4565G>T	p.Ser1522Ile	missense_variant	Exon 40 of 43		XP_011512254.1
MROH2B	XM_011513953.2 link	c.4379G>T	p.Ser1460Ile	missense_variant	Exon 39 of 41		XP_011512255.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MROH2B	ENST00000399564.5 link	c.4565G>T	p.Ser1522Ile	missense_variant	Exon 40 of 42	1	NM_173489.5	ENSP00000382476.4		Q7Z745-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000805

AC:

AN:

248570

Hom.:

AF XY:

0.00000742

AC XY:

AN XY:

134790

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000888

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460820

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726556

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Uncertain

0.023

BayesDel_noAF

Benign

-0.10

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.033

T;T

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.74

T;T

M_CAP

Benign

0.018

MetaRNN

Uncertain

0.70

D;D

MetaSVM

Benign

-0.65

MutationAssessor

Benign

1.7

.;L

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.51

N;N

REVEL

Benign

0.28

Sift

Benign

0.30

T;T

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.99

.;D

Vest4

0.72

MutPred

0.53

.;Loss of catalytic residue at S1522 (P = 0.0369);

MVP

0.27

MPC

0.18

ClinPred

0.85

GERP RS

4.8

Varity_R

0.20

gMVP

0.42

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