5-41018350-A-T

Variant summary

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

The NM_173489.5(MROH2B):c.2754T>A(p.Asn918Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.353 in 1,610,804 control chromosomes in the GnomAD database, including 101,590 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 0.35 (9338 hom., cov: 33)
  • Exomes 𝑓: 0.35 (92252 hom.)
• Consequence: MROH2B NM_173489.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0650

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=0.0017885566).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.416 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MROH2B	NM_173489.5	c.2754T>A	p.Asn918Lys	missense_variant	27/42	ENST00000399564.5
MROH2B	XM_011513952.2	c.2754T>A	p.Asn918Lys	missense_variant	27/43
MROH2B	XM_011513953.2	c.2568T>A	p.Asn856Lys	missense_variant	26/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MROH2B	ENST00000399564.5	c.2754T>A	p.Asn918Lys	missense_variant	27/42	1	NM_173489.5	P1

Frequencies

GnomAD3 genomes AF: 0.347 AC: 52802 AN: 151986 Hom.: 9333 Cov.: 33

Gnomad AFR AF: 0.348

Gnomad AMI AF: 0.210

Gnomad AMR AF: 0.393

Gnomad ASJ AF: 0.357

Gnomad EAS AF: 0.285

Gnomad SAS AF: 0.431

Gnomad FIN AF: 0.291

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.346

Gnomad OTH AF: 0.342

GnomAD3 exomes AF: 0.357 AC: 87376 AN: 245078 Hom.: 15846 AF XY: 0.361 AC XY: 47922 AN XY: 132714

Gnomad AFR exome AF: 0.345

Gnomad AMR exome AF: 0.407

Gnomad ASJ exome AF: 0.350

Gnomad EAS exome AF: 0.280

Gnomad SAS exome AF: 0.439

Gnomad FIN exome AF: 0.292

Gnomad NFE exome AF: 0.346

Gnomad OTH exome AF: 0.355

GnomAD4 exome AF: 0.354 AC: 516083 AN: 1458700 Hom.: 92252 Cov.: 36 AF XY: 0.356 AC XY: 258454 AN XY: 725358

Gnomad4 AFR exome AF: 0.346

Gnomad4 AMR exome AF: 0.406

Gnomad4 ASJ exome AF: 0.350

Gnomad4 EAS exome AF: 0.274

Gnomad4 SAS exome AF: 0.446

Gnomad4 FIN exome AF: 0.289

Gnomad4 NFE exome AF: 0.351

Gnomad4 OTH exome AF: 0.359

GnomAD4 genome AF: 0.347 AC: 52843 AN: 152104 Hom.: 9338 Cov.: 33 AF XY: 0.348 AC XY: 25848 AN XY: 74358

Gnomad4 AFR AF: 0.348

Gnomad4 AMR AF: 0.393

Gnomad4 ASJ AF: 0.357

Gnomad4 EAS AF: 0.285

Gnomad4 SAS AF: 0.432

Gnomad4 FIN AF: 0.291

Gnomad4 NFE AF: 0.346

Gnomad4 OTH AF: 0.341

Alfa AF: 0.310 Hom.: 2438

Bravo AF: 0.354

TwinsUK AF: 0.352 AC: 1304

ALSPAC AF: 0.349 AC: 1344

ESP6500AA AF: 0.337 AC: 1262

ESP6500EA AF: 0.335 AC: 2751

ExAC AF: 0.352 AC: 42493

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	0.73
Dann	Benign	0.85
DEOGEN2	Benign	0.0030	T;T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.44	T;T
MetaRNN	Benign	0.0018	T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.31	N;N
REVEL	Benign	0.021
Sift	Benign	0.28	T;T
Sift4G	Benign	0.20	T;T
Polyphen		0.0010	.;B
Vest4		0.099
MutPred		0.28		.;Gain of ubiquitination at N918 (P = 0.0369);
MPC		0.022
ClinPred		0.00043	T
GERP RS		2.2
Varity_R		0.048
gMVP		0.19

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: rs10054110; hg19: chr5-41018452; COSMIC: COSV68181938;