5-41000232-G-T

Variant summary

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

The NM_173489.5(MROH2B):c.4470C>A(p.Phe1490Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000706 in 1,613,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000064 (0 hom.)
• Consequence: MROH2B NM_173489.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.512

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.041218787).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MROH2B	NM_173489.5	c.4470C>A	p.Phe1490Leu	missense_variant	39/42	ENST00000399564.5
MROH2B	XM_011513952.2	c.4470C>A	p.Phe1490Leu	missense_variant	39/43
MROH2B	XM_011513953.2	c.4284C>A	p.Phe1428Leu	missense_variant	38/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MROH2B	ENST00000399564.5	c.4470C>A	p.Phe1490Leu	missense_variant	39/42	1	NM_173489.5	P1

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000885 AC: 22 AN: 248654 Hom.: 0 AF XY: 0.0000742 AC XY: 10 AN XY: 134842

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: 0.00

Gnomad FIN exome AF: 0.000464

Gnomad NFE exome AF: 0.0000978

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000643 AC: 94 AN: 1461590 Hom.: 0 Cov.: 31 AF XY: 0.0000701 AC XY: 51 AN XY: 727072

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: 0.00

Gnomad4 FIN exome AF: 0.000318

Gnomad4 NFE exome AF: 0.0000666

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 74326

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000112 Hom.: 0

Bravo AF: 0.0000831

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.0000579 AC: 7

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

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 09, 2021

The c.4470C>A (p.F1490L) alteration is located in exon 39 (coding exon 39) of the MROH2B gene. This alteration results from a C to A substitution at nucleotide position 4470, causing the phenylalanine (F) at amino acid position 1490 to be replaced by a leucine (L). 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	Uncertain	0.53
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	14
Dann	Benign	0.55
DEOGEN2	Benign	0.0067	T;T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.59	T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.041	T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	0.65	D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.83	N;N
REVEL	Benign	0.064
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	.;B
Vest4		0.31
MutPred		0.38		.;Loss of MoRF binding (P = 0.1197);
MVP		0.048
MPC		0.022
ClinPred		0.077	T
GERP RS		3.1
Varity_R		0.065
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs200676167; hg19: chr5-41000334; COSMIC: COSV68189339; COSMIC: COSV68189339;