Genetic Variant ROPN1B:p.Glu39Gln (chr3-125972169-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001308313.2(ROPN1B):c.115G>C(p.Asp39His) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000173 in 1,613,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

ROPN1B
NM_001308313.2 missense, splice_region

Scores

Splicing: ADA: 0.006883

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.10

Variant links:

Genes affected

ROPN1B (HGNC:31927): (rhophilin associated tail protein 1B) Enables protein heterodimerization activity. Predicted to be involved in several processes, including flagellated sperm motility; protein localization to cilium; and sperm capacitation. Located in cytoplasm and motile cilium. [provided by Alliance of Genome Resources, Apr 2022]

ROPN1B links:

ALG1L1P (HGNC:33721): (ALG1 like 1, pseudogene) Predicted to enable mannosyltransferase activity. Predicted to be involved in protein glycosylation. Predicted to be active in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

ALG1L1P links:

ENSG00000291096 (HGNC:):

ENSG00000291096 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.25442517).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROPN1B	NM_001308313.2 link	c.115G>C	p.Asp39His	missense_variant, splice_region_variant	Exon 3 of 7	ENST00000514116.6	NP_001295242.1	Q9BZX4-1A0A140VKG6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ROPN1B	ENST00000514116.6 link	c.115G>C	p.Asp39His	missense_variant, splice_region_variant	Exon 3 of 7	1	NM_001308313.2	ENSP00000426271.1		Q9BZX4-1

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251212

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135802

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461766

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727188

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.0000224

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000105

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.000362

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.000125

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 20, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.115G>C (p.D39H) alteration is located in exon 2 (coding exon 1) of the ROPN1B gene. This alteration results from a G to C substitution at nucleotide position 115, causing the aspartic acid (D) at amino acid position 39 to be replaced by a histidine (H). 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

0.16

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.028

T;T;.;T

Eigen

Benign

-0.024

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.84

.;T;D;D

M_CAP

Benign

0.014

MetaRNN

Benign

0.25

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

L;L;.;.

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.79

N;N;N;N

REVEL

Benign

0.19

Sift

Benign

0.071

T;T;D;D

Sift4G

Benign

0.073

T;T;T;T

Polyphen

0.94

P;P;.;.

Vest4

0.47

MVP

0.85

MPC

0.26

ClinPred

0.17

GERP RS

3.4

Varity_R

0.16

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0069

dbscSNV1_RF

Benign

0.052

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over