5-41008678-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.83 (52263 hom., cov: 32)
  • Exomes 𝑓: 0.82 (489762 hom.)
• Consequence: MROH2B NM_173489.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.82

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 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/exons	MANE	UniProt
MROH2B	NM_173489.5	c.3536T>C	p.Leu1179Pro	missense_variant	33/42	ENST00000399564.5
MROH2B	XM_011513952.2	c.3536T>C	p.Leu1179Pro	missense_variant	33/43
MROH2B	XM_011513953.2	c.3350T>C	p.Leu1117Pro	missense_variant	32/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MROH2B	ENST00000399564.5	c.3536T>C	p.Leu1179Pro	missense_variant	33/42	1	NM_173489.5	P1

Frequencies

GnomAD3 genomes AF: 0.827 AC: 125691 AN: 152016 Hom.: 52216 Cov.: 32

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

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.: 63 AF XY: 0.817 AC XY: 593956 AN XY: 727048

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.: 32 AF XY: 0.824 AC XY: 61297 AN XY: 74378

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	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	16
Dann	Benign	0.067
DEOGEN2	Benign	0.0033	T;T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.22	T;T
MetaRNN	Benign	0.0000015	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.50	P;P
PrimateAI	Benign	0.40	T
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	T
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

Other links and lift over

dbSNP: rs2271704; hg19: chr5-41008780;