5-41000281-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_173489.5(MROH2B):c.4421G>A(p.Arg1474His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000136 in 1,613,694 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: MROH2B NM_173489.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.670

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.045470566).
• BP6: Variant 5-41000281-C-T is Benign according to our data. Variant chr5-41000281-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2369066.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MROH2B	NM_173489.5	c.4421G>A	p.Arg1474His	missense_variant	39/42	ENST00000399564.5
MROH2B	XM_011513952.2	c.4421G>A	p.Arg1474His	missense_variant	39/43
MROH2B	XM_011513953.2	c.4235G>A	p.Arg1412His	missense_variant	38/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MROH2B	ENST00000399564.5	c.4421G>A	p.Arg1474His	missense_variant	39/42	1	NM_173489.5	P1

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152104 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000189 AC: 47 AN: 248638 Hom.: 0 AF XY: 0.000156 AC XY: 21 AN XY: 134858

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000276

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000126 AC: 184 AN: 1461590 Hom.: 1 Cov.: 35 AF XY: 0.000116 AC XY: 84 AN XY: 727086

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000130

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.000237 AC: 36 AN: 152104 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74296

Gnomad4 AFR AF: 0.000266

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000206 Hom.: 0

Bravo AF: 0.000193

ESP6500AA AF: 0.000268 AC: 1

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.000327

EpiControl AF: 0.000178

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	12
Dann	Benign	0.67
DEOGEN2	Benign	0.0053	T;T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.52	T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.045	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.33	N;N
REVEL	Benign	0.033
Sift	Benign	0.54	T;T
Sift4G	Benign	0.60	T;T
Polyphen		0.0010	.;B
Vest4		0.13
MVP		0.030
MPC		0.022
ClinPred		0.030	T
GERP RS		0.39
Varity_R		0.029
gMVP		0.10

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

Other links and lift over

dbSNP: rs189708836; hg19: chr5-41000383; COSMIC: COSV68187984; COSMIC: COSV68187984;