5-40998617-G-T

Position:

• chr5-40998617-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000399564.5(MROH2B):​c.4646C>A​(p.Thr1549Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MROH2B ENST00000399564.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.583

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21054047).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MROH2B	NM_173489.5	c.4646C>A	p.Thr1549Asn	missense_variant	41/42	ENST00000399564.5	NP_775760.3
MROH2B	XM_011513952.2	c.4646C>A	p.Thr1549Asn	missense_variant	41/43		XP_011512254.1
MROH2B	XM_011513953.2	c.4460C>A	p.Thr1487Asn	missense_variant	40/41		XP_011512255.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MROH2B	ENST00000399564.5	c.4646C>A	p.Thr1549Asn	missense_variant	41/42	1	NM_173489.5	ENSP00000382476	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1442976 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 715630

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: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Dec 17, 2023

The c.4646C>A (p.T1549N) alteration is located in exon 41 (coding exon 41) of the MROH2B gene. This alteration results from a C to A substitution at nucleotide position 4646, causing the threonine (T) at amino acid position 1549 to be replaced by an asparagine (N). 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	Benign	0.093
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	11
DANN	Benign	0.62
DEOGEN2	Benign	0.028	T;T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.68	T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.9	.;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.73	N;N
REVEL	Benign	0.072
Sift	Benign	0.49	T;T
Sift4G	Benign	0.22	T;T
Polyphen		0.63	.;P
Vest4		0.51
MutPred		0.26		.;Loss of loop (P = 0.1242);
MVP		0.095
MPC		0.079
ClinPred		0.21	T
GERP RS		1.8
Varity_R		0.038
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1346979998; hg19: chr5-40998719;