5-41008655-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_173489.5(MROH2B):c.3559C>T(p.Arg1187Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000039 in 1,613,772 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: MROH2B NM_173489.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.56

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07739836).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MROH2B	NM_173489.5	c.3559C>T	p.Arg1187Trp	missense_variant	33/42	ENST00000399564.5
MROH2B	XM_011513952.2	c.3559C>T	p.Arg1187Trp	missense_variant	33/43
MROH2B	XM_011513953.2	c.3373C>T	p.Arg1125Trp	missense_variant	32/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MROH2B	ENST00000399564.5	c.3559C>T	p.Arg1187Trp	missense_variant	33/42	1	NM_173489.5	P1

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152156 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.0000442 AC: 11 AN: 248798 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 134932

Gnomad AFR exome AF: 0.000581

Gnomad AMR exome AF: 0.0000580

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000260 AC: 38 AN: 1461616 Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16 AN XY: 727074

Gnomad4 AFR exome AF: 0.000836

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: 0.00000540

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152156 Hom.: 1 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74334

Gnomad4 AFR AF: 0.000531

Gnomad4 AMR AF: 0.000196

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: 0.0000987 Hom.: 0

Bravo AF: 0.000196

ESP6500AA AF: 0.000484 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000331 AC: 4

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

Jul 20, 2021

The c.3559C>T (p.R1187W) alteration is located in exon 33 (coding exon 33) of the MROH2B gene. This alteration results from a C to T substitution at nucleotide position 3559, causing the arginine (R) at amino acid position 1187 to be replaced by a tryptophan (W). 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	0.11
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.025	T;T
Eigen	Benign	-0.090
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.082	N
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.077	T;T
MetaSVM	Benign	-0.87	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.19	N;N
REVEL	Benign	0.21
Sift	Benign	0.18	T;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.51
MVP		0.067
MPC		0.17
ClinPred		0.17	T
GERP RS		4.0
Varity_R		0.086
gMVP		0.25

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

Other links and lift over

dbSNP: rs369303264; hg19: chr5-41008757; COSMIC: COSV68181030;