5-41018350-A-T

Variant names:

• chr5-41018350-A-T
• rs10054110
• NM_173489.5:c.2754T>A

Variant summary

Our verdict is Benign. The variant received -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. 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 0.35 (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
• Publications: 30 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 (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 rank	MANE	Protein	UniProt
MROH2B	NM_173489.5	c.2754T>A	p.Asn918Lys	missense_variant	Exon 27 of 42	ENST00000399564.5	NP_775760.3
MROH2B	XM_011513952.2	c.2754T>A	p.Asn918Lys	missense_variant	Exon 27 of 43		XP_011512254.1
MROH2B	XM_011513953.2	c.2568T>A	p.Asn856Lys	missense_variant	Exon 26 of 41		XP_011512255.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MROH2B	ENST00000399564.5	c.2754T>A	p.Asn918Lys	missense_variant	Exon 27 of 42	1	NM_173489.5	ENSP00000382476.4

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

GnomAD2 exomes AF: 0.357 AC: 87376 AN: 245078 AF XY: 0.361

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 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

African (AFR) AF: 0.346 AC: 11576 AN: 33460

American (AMR) AF: 0.406 AC: 17991 AN: 44266

Ashkenazi Jewish (ASJ) AF: 0.350 AC: 9128 AN: 26078

East Asian (EAS) AF: 0.274 AC: 10876 AN: 39636

South Asian (SAS) AF: 0.446 AC: 38262 AN: 85710

European-Finnish (FIN) AF: 0.289 AC: 15348 AN: 53154

Middle Eastern (MID) AF: 0.353 AC: 2035 AN: 5762

European-Non Finnish (NFE) AF: 0.351 AC: 389213 AN: 1110348

Other (OTH) AF: 0.359 AC: 21654 AN: 60286

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

African (AFR) AF: 0.348 AC: 14439 AN: 41466

American (AMR) AF: 0.393 AC: 6012 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.357 AC: 1239 AN: 3472

East Asian (EAS) AF: 0.285 AC: 1470 AN: 5164

South Asian (SAS) AF: 0.432 AC: 2084 AN: 4826

European-Finnish (FIN) AF: 0.291 AC: 3082 AN: 10580

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.346 AC: 23499 AN: 67986

Other (OTH) AF: 0.341 AC: 719 AN: 2106

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
MutationAssessor	Benign	1.3	.;L
PhyloP100		0.065
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
Mutation Taster		=97/3	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: rs10054110; hg19: chr5-41018452; COSMIC: COSV68181938;