Genetic Variant ROPN1B:p.Thr114Met (chr3-125977110-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001308313.2(ROPN1B):c.341C>T(p.Thr114Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000432 in 150,474 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 29)

Exomes 𝑓: 0.00057 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

ROPN1B
NM_001308313.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.687

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 Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01631406).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROPN1B	NM_001308313.2 link	c.341C>T	p.Thr114Met	missense_variant	Exon 5 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.341C>T	p.Thr114Met	missense_variant	Exon 5 of 7	1	NM_001308313.2	ENSP00000426271.1		Q9BZX4-1

Frequencies

GnomAD3 genomes

AF:

0.000432

AC:

AN:

150356

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000742

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000670

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000782

Gnomad OTH

AF:

0.000491

GnomAD3 exomes

AF:

0.000606

AC:

100

AN:

165046

Hom.:

AF XY:

0.000671

AC XY:

AN XY:

87992

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000828

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000638

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000241

Gnomad NFE exome

AF:

0.00126

Gnomad OTH exome

AF:

0.000497

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000573

AC:

568

AN:

990842

Hom.:

Cov.:

AF XY:

0.000540

AC XY:

276

AN XY:

510646

show subpopulations

Gnomad4 AFR exome

AF:

0.0000888

Gnomad4 AMR exome

AF:

0.000119

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000530

Gnomad4 SAS exome

AF:

0.0000137

Gnomad4 FIN exome

AF:

0.000728

Gnomad4 NFE exome

AF:

0.000712

Gnomad4 OTH exome

AF:

0.000602

GnomAD4 genome

AF:

0.000432

AC:

AN:

150474

Hom.:

Cov.:

AF XY:

0.000449

AC XY:

AN XY:

73474

show subpopulations

Gnomad4 AFR

AF:

0.0000740

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000670

Gnomad4 NFE

AF:

0.000782

Gnomad4 OTH

AF:

0.000486

Alfa

AF:

0.000475

Hom.:

Bravo

AF:

0.000340

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000400

AC:

ExAC

AF:

0.000753

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.341C>T (p.T114M) alteration is located in exon 4 (coding exon 3) of the ROPN1B gene. This alteration results from a C to T substitution at nucleotide position 341, causing the threonine (T) at amino acid position 114 to be replaced by a methionine (M). 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

0.092

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.0081

T;T;.;.;.

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.67

.;T;T;.;T

M_CAP

Benign

0.0084

MetaRNN

Benign

0.016

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

L;L;.;.;.

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.80

N;N;N;N;N

REVEL

Benign

0.14

Sift

Benign

0.095

T;T;T;T;T

Sift4G

Benign

0.098

T;T;T;T;T

Polyphen

0.053

B;B;.;.;.

Vest4

0.11

MVP

0.29

MPC

2.0

ClinPred

0.029

GERP RS

2.7

Varity_R

0.027

gMVP

0.46

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

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