Genetic Variant ROPN1B:p.Trp64Arg (chr3-125975636-T-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001308313.2(ROPN1B):c.190T>A(p.Trp64Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000076 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ROPN1B
NM_001308313.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.17

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.27819064).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001308313.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ROPN1B	NM_001308313.2	MANE Select	c.190T>A	p.Trp64Arg	missense	Exon 4 of 7	NP_001295242.1	A0A140VKG6
ROPN1B	NM_001012337.3		c.190T>A	p.Trp64Arg	missense	Exon 3 of 6	NP_001012337.1	A0A140VKG6
ALG1L1P	NR_171196.1		n.116+14786A>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ROPN1B	ENST00000514116.6	TSL:1 MANE Select	c.190T>A	p.Trp64Arg	missense	Exon 4 of 7	ENSP00000426271.1	Q9BZX4-1
ROPN1B	ENST00000251776.8	TSL:1	c.190T>A	p.Trp64Arg	missense	Exon 3 of 6	ENSP00000251776.4	Q9BZX4-1
ROPN1B	ENST00000513830.5	TSL:2	c.190T>A	p.Trp64Arg	missense	Exon 5 of 6	ENSP00000425548.1	D6RCR2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000764

AC:

AN:

1440670

Hom.:

Cov.:

AF XY:

0.00000697

AC XY:

AN XY:

717016

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000613

AC:

AN:

32646

American (AMR)

AF:

0.00

AC:

AN:

44080

Ashkenazi Jewish (ASJ)

AF:

0.0000399

AC:

AN:

25088

East Asian (EAS)

AF:

0.00

AC:

AN:

37886

South Asian (SAS)

AF:

0.00

AC:

AN:

86038

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51498

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5638

European-Non Finnish (NFE)

AF:

0.00000546

AC:

AN:

1098978

Other (OTH)

AF:

0.0000340

AC:

AN:

58818

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.234

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.0095

Eigen

Benign

-0.071

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.44

M_CAP

Benign

0.011

MetaRNN

Benign

0.28

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

PhyloP100

4.2

PrimateAI

Uncertain

0.67

PROVEAN

Benign

2.0

REVEL

Benign

0.21

Sift

Benign

0.56

Sift4G

Benign

0.57

Polyphen

1.0

Vest4

0.76

MutPred

0.47

Gain of loop (P = 0.0045)

MVP

0.57

MPC

0.61

ClinPred

0.75

GERP RS

2.8

PromoterAI

0.013

Neutral

(source)

Varity_R

0.10

gMVP

0.55

Mutation Taster

=74/26

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over