5-41008678-A-G

Variant names:

• chr5-41008678-A-G
• rs2271704
• NM_173489.5:c.3536T>C

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 33 publications found

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]

C7 Gene-Disease associations (from GenCC):

• complement component 7 deficiency

  Inheritance: AR Classification: STRONG Submitted by: Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173489.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MROH2B	NM_173489.5	MANE Select	c.3536T>C	p.Leu1179Pro	missense	Exon 33 of 42	NP_775760.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MROH2B	ENST00000399564.5	TSL:1 MANE Select	c.3536T>C	p.Leu1179Pro	missense	Exon 33 of 42	ENSP00000382476.4	Q7Z745-1
	MROH2B	ENST00000506092.6	TSL:2	c.2201T>C	p.Leu734Pro	missense	Exon 23 of 32	ENSP00000441504.1	F5GZ06
	MROH2B	ENST00000503890.5	TSL:2	n.2498T>C		non_coding_transcript_exon	Exon 21 of 31

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

GnomAD2 exomes AF: 0.804 AC: 199930 AN: 248692 AF XY: 0.804

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 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

African (AFR) AF: 0.880 AC: 29457 AN: 33476

American (AMR) AF: 0.845 AC: 37786 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.788 AC: 20584 AN: 26132

East Asian (EAS) AF: 0.657 AC: 26054 AN: 39678

South Asian (SAS) AF: 0.803 AC: 69227 AN: 86242

European-Finnish (FIN) AF: 0.773 AC: 41292 AN: 53400

Middle Eastern (MID) AF: 0.818 AC: 4718 AN: 5768

European-Non Finnish (NFE) AF: 0.825 AC: 917250 AN: 1111796

Other (OTH) AF: 0.806 AC: 48651 AN: 60368

GnomAD4 genome AF: 0.827 AC: 125797 AN: 152134 Hom.: 52263 Cov.: 32 AF XY: 0.824 AC XY: 61297 AN XY: 74378

African (AFR) AF: 0.874 AC: 36264 AN: 41514

American (AMR) AF: 0.862 AC: 13167 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.797 AC: 2768 AN: 3472

East Asian (EAS) AF: 0.632 AC: 3263 AN: 5160

South Asian (SAS) AF: 0.787 AC: 3792 AN: 4818

European-Finnish (FIN) AF: 0.765 AC: 8088 AN: 10576

Middle Eastern (MID) AF: 0.762 AC: 224 AN: 294

European-Non Finnish (NFE) AF: 0.822 AC: 55866 AN: 67994

Other (OTH) AF: 0.822 AC: 1740 AN: 2116

Alfa AF: 0.821 Hom.: 257015

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 v4.9

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
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.22	T
MetaRNN	Benign	0.0000015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.7	N
PhyloP100		1.8
PrimateAI	Benign	0.40	T
PROVEAN	Benign	5.2	N
REVEL	Benign	0.065
Sift	Benign	1.0	T
Sift4G	Benign	1.0	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
Mutation Taster		=92/8	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2271704; hg19: chr5-41008780; COSMIC: COSV107507181;