NM_173489.5:c.4194+649A>G

Variant names:

• chr5-41003697-T-C
• rs10512754
• NM_173489.5:c.4194+649A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_173489.5(MROH2B):​c.4194+649A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.447 in 152,026 control chromosomes in the GnomAD database, including 15,475 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 0.45 (15475 hom., cov: 32)
• Consequence: MROH2B NM_173489.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.186
• Publications: 6 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: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.497 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MROH2B	NM_173489.5	c.4194+649A>G		intron_variant	Intron 37 of 41	ENST00000399564.5	NP_775760.3
MROH2B	XM_011513952.2	c.4194+649A>G		intron_variant	Intron 37 of 42		XP_011512254.1
MROH2B	XM_011513953.2	c.4008+649A>G		intron_variant	Intron 36 of 40		XP_011512255.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MROH2B	ENST00000399564.5	c.4194+649A>G		intron_variant	Intron 37 of 41	1	NM_173489.5	ENSP00000382476.4

Frequencies

GnomAD3 genomes AF: 0.447 AC: 67954 AN: 151908 Hom.: 15467 Cov.: 32

Gnomad AFR AF: 0.503

Gnomad AMI AF: 0.454

Gnomad AMR AF: 0.443

Gnomad ASJ AF: 0.382

Gnomad EAS AF: 0.283

Gnomad SAS AF: 0.282

Gnomad FIN AF: 0.448

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.442

Gnomad OTH AF: 0.449

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.447 AC: 67996 AN: 152026 Hom.: 15475 Cov.: 32 AF XY: 0.443 AC XY: 32938 AN XY: 74296

African (AFR) AF: 0.502 AC: 20821 AN: 41440

American (AMR) AF: 0.443 AC: 6766 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.382 AC: 1326 AN: 3468

East Asian (EAS) AF: 0.284 AC: 1468 AN: 5162

South Asian (SAS) AF: 0.282 AC: 1357 AN: 4814

European-Finnish (FIN) AF: 0.448 AC: 4740 AN: 10590

Middle Eastern (MID) AF: 0.333 AC: 98 AN: 294

European-Non Finnish (NFE) AF: 0.442 AC: 30068 AN: 67966

Other (OTH) AF: 0.445 AC: 938 AN: 2110

Alfa AF: 0.436 Hom.: 7524

Bravo AF: 0.449

Asia WGS AF: 0.270 AC: 938 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	9.9
DANN	Benign	0.70
PhyloP100		0.19
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: rs10512754; hg19: chr5-41003799;