5-40998133-C-T

Variant names:

• chr5-40998133-C-T
• rs722575
• NM_173489.5:c.4677G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_173489.5(MROH2B):​c.4677G>A​(p.Pro1559Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.39 in 1,600,780 control chromosomes in the GnomAD database, including 124,677 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.37 (10793 hom., cov: 32)
  • Exomes 𝑓: 0.39 (113884 hom.)
• Consequence: MROH2B NM_173489.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.636
• Publications: 15 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP7: Synonymous conserved (PhyloP=-0.636 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.404 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.4677G>A	p.Pro1559Pro	synonymous	Exon 42 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.4677G>A	p.Pro1559Pro	synonymous	Exon 42 of 42	ENSP00000382476.4	Q7Z745-1
	MROH2B	ENST00000511934.5	TSL:1	n.484G>A		non_coding_transcript_exon	Exon 3 of 3
	MROH2B	ENST00000506092.6	TSL:2	c.3342G>A	p.Pro1114Pro	synonymous	Exon 32 of 32	ENSP00000441504.1	F5GZ06

Frequencies

GnomAD3 genomes AF: 0.372 AC: 56518 AN: 151924 Hom.: 10788 Cov.: 32

Gnomad AFR AF: 0.309

Gnomad AMI AF: 0.380

Gnomad AMR AF: 0.383

Gnomad ASJ AF: 0.315

Gnomad EAS AF: 0.291

Gnomad SAS AF: 0.304

Gnomad FIN AF: 0.463

Gnomad MID AF: 0.298

Gnomad NFE AF: 0.408

Gnomad OTH AF: 0.367

GnomAD2 exomes AF: 0.375 AC: 92438 AN: 246424 AF XY: 0.372

Gnomad AFR exome AF: 0.308

Gnomad AMR exome AF: 0.382

Gnomad ASJ exome AF: 0.315

Gnomad EAS exome AF: 0.297

Gnomad FIN exome AF: 0.468

Gnomad NFE exome AF: 0.400

Gnomad OTH exome AF: 0.370

GnomAD4 exome AF: 0.392 AC: 567747 AN: 1448736 Hom.: 113884 Cov.: 33 AF XY: 0.390 AC XY: 280873 AN XY: 721066

African (AFR) AF: 0.307 AC: 10172 AN: 33150

American (AMR) AF: 0.382 AC: 16878 AN: 44188

Ashkenazi Jewish (ASJ) AF: 0.320 AC: 8314 AN: 25954

East Asian (EAS) AF: 0.312 AC: 12320 AN: 39512

South Asian (SAS) AF: 0.306 AC: 26147 AN: 85456

European-Finnish (FIN) AF: 0.465 AC: 24726 AN: 53132

Middle Eastern (MID) AF: 0.355 AC: 2031 AN: 5720

European-Non Finnish (NFE) AF: 0.404 AC: 444875 AN: 1101738

Other (OTH) AF: 0.372 AC: 22284 AN: 59886

GnomAD4 genome AF: 0.372 AC: 56545 AN: 152044 Hom.: 10793 Cov.: 32 AF XY: 0.373 AC XY: 27712 AN XY: 74320

African (AFR) AF: 0.309 AC: 12806 AN: 41452

American (AMR) AF: 0.384 AC: 5857 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.315 AC: 1092 AN: 3468

East Asian (EAS) AF: 0.293 AC: 1511 AN: 5160

South Asian (SAS) AF: 0.304 AC: 1467 AN: 4824

European-Finnish (FIN) AF: 0.463 AC: 4890 AN: 10572

Middle Eastern (MID) AF: 0.279 AC: 81 AN: 290

European-Non Finnish (NFE) AF: 0.408 AC: 27727 AN: 67982

Other (OTH) AF: 0.362 AC: 767 AN: 2116

Alfa AF: 0.379 Hom.: 21758

Bravo AF: 0.362

Asia WGS AF: 0.271 AC: 942 AN: 3478

EpiCase AF: 0.401

EpiControl AF: 0.397

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	0.39
DANN	Benign	0.36
PhyloP100		-0.64
Mutation Taster		=100/0	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: rs722575; hg19: chr5-40998235; COSMIC: COSV68181071;