3-125983264-G-T

Position:

• chr3-125983264-G-T

Variant summary

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

The NM_001308313.2(ROPN1B):​c.583G>T​(p.Asp195Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,500 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ROPN1B NM_001308313.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.76

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]

ALG1L1P (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ROPN1B	NM_001308313.2	c.583G>T	p.Asp195Tyr	missense_variant	7/7	ENST00000514116.6	NP_001295242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ROPN1B	ENST00000514116.6	c.583G>T	p.Asp195Tyr	missense_variant	7/7	1	NM_001308313.2	ENSP00000426271.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460500 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726648

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: 0.0000166

GnomAD4 genome Cov.: 32

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

Nov 08, 2022

The c.583G>T (p.D195Y) alteration is located in exon 6 (coding exon 5) of the ROPN1B gene. This alteration results from a G to T substitution at nucleotide position 583, causing the aspartic acid (D) at amino acid position 195 to be replaced by a tyrosine (Y). 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	0.21
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.091	T;T;.;.
Eigen	Uncertain	0.33
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.81	.;T;.;T
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.68	D;D;D;D
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.2	M;M;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-4.6	D;D;D;D
REVEL	Benign	0.21
Sift	Uncertain	0.010	D;D;D;D
Sift4G	Uncertain	0.022	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.64
MutPred		0.38		Loss of loop (P = 0.0804);Loss of loop (P = 0.0804);.;.;
MVP		0.47
MPC		1.1
ClinPred		0.99	D
GERP RS		2.2
Varity_R		0.36
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs1357720887; hg19: chr3-125702107;