3-125983256-T-C

Variant names:

• chr3-125983256-T-C
• rs552696492
• NM_001308313.2:c.575T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001308313.2(ROPN1B):​c.575T>C​(p.Ile192Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000186 in 1,610,934 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ROPN1B NM_001308313.2 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.80
• Publications: 0 publications found

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: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]

ENSG00000291096 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROPN1B	NM_001308313.2	MANE Select	c.575T>C	p.Ile192Thr	missense splice_region	Exon 7 of 7	NP_001295242.1	A0A140VKG6
	ROPN1B	NM_001012337.3		c.575T>C	p.Ile192Thr	missense splice_region	Exon 6 of 6	NP_001012337.1	A0A140VKG6
	ALG1L1P	NR_171196.1		n.116+7166A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROPN1B	ENST00000514116.6	TSL:1 MANE Select	c.575T>C	p.Ile192Thr	missense splice_region	Exon 7 of 7	ENSP00000426271.1	Q9BZX4-1
	ROPN1B	ENST00000251776.8	TSL:1	c.575T>C	p.Ile192Thr	missense splice_region	Exon 6 of 6	ENSP00000251776.4	Q9BZX4-1
	ROPN1B	ENST00000505382.5	TSL:2	c.299T>C	p.Ile100Thr	missense splice_region	Exon 4 of 4	ENSP00000421662.1	Q9BZX4-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251170 AF XY: 0.00000737

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458626 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 725896

African (AFR) AF: 0.00 AC: 0 AN: 33402

American (AMR) AF: 0.00 AC: 0 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.00 AC: 0 AN: 86116

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1109206

Other (OTH) AF: 0.00 AC: 0 AN: 60294

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152308 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74488

African (AFR) AF: 0.0000241 AC: 1 AN: 41554

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2116

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.0013	T
Eigen	Benign	0.091
Eigen_PC	Benign	0.025
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0044	T
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		3.8
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	0.040	N
REVEL	Benign	0.13
Sift	Benign	0.57	T
Sift4G	Benign	0.57	T
Polyphen		0.96	D
Vest4		0.64
MutPred		0.27		Loss of stability (P = 0.0175)
MVP		0.47
MPC		0.42
ClinPred		0.25	T
GERP RS		2.2
Varity_R		0.047
gMVP		0.36
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs552696492; hg19: chr3-125702099;