Variant 19-48741443-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_182575.3(IZUMO1):c.790C>T(p.Pro264Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00175 in 1,612,706 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 6 hom. )

Consequence

IZUMO1
NM_182575.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.947

Variant links:

Genes affected

IZUMO1 (HGNC:28539): (izumo sperm-oocyte fusion 1) The sperm-specific protein Izumo, named for a Japanese shrine dedicated to marriage, is essential for sperm-egg plasma membrane binding and fusion (Inoue et al., 2005 [PubMed 15759005]).[supplied by OMIM, Mar 2008]

IZUMO1 links:

IZUMO1 (HGNC:):

IZUMO1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008383781).

BS2

High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IZUMO1	NM_182575.3 linkuse as main transcript	c.790C>T	p.Pro264Ser	missense_variant	9/10	ENST00000332955.7	NP_872381.2	Q8IYV9-1
IZUMO1	NM_001321864.1 linkuse as main transcript	c.451C>T	p.Pro151Ser	missense_variant	8/9		NP_001308793.1
IZUMO1	NM_001321865.1 linkuse as main transcript	c.268C>T	p.Pro90Ser	missense_variant	8/9		NP_001308794.1	Q8IYV9
IZUMO1	NR_135832.1 linkuse as main transcript	n.826C>T		non_coding_transcript_exon_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IZUMO1	ENST00000332955.7 linkuse as main transcript	c.790C>T	p.Pro264Ser	missense_variant	9/10	1	NM_182575.3	ENSP00000327786.2		Q8IYV9-1

Frequencies

GnomAD3 genomes

AF:

0.00104

AC:

159

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000289

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000392

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00200

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000983

AC:

247

AN:

251396

Hom.:

AF XY:

0.00102

AC XY:

138

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.000595

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.00186

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.00182

AC:

2662

AN:

1460336

Hom.:

Cov.:

AF XY:

0.00178

AC XY:

1293

AN XY:

726172

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.000358

Gnomad4 ASJ exome

AF:

0.000651

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00226

Gnomad4 OTH exome

AF:

0.00149

GnomAD4 genome

AF:

0.00104

AC:

159

AN:

152370

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

AN XY:

74512

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00200

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00170

Hom.:

Bravo

AF:

0.00109

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00209

AC:

ExAC

AF:

0.000791

AC:

EpiCase

AF:

0.00191

EpiControl

AF:

0.00225

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 07, 2024

The c.790C>T (p.P264S) alteration is located in exon 9 (coding exon 8) of the IZUMO1 gene. This alteration results from a C to T substitution at nucleotide position 790, causing the proline (P) at amino acid position 264 to be replaced by a serine (S). 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

-0.62

BayesDel_noAF

Benign

-0.67

CADD

Benign

0.20

DANN

Benign

0.88

DEOGEN2

Uncertain

0.52

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.65

M_CAP

Benign

0.0052

MetaRNN

Benign

0.0084

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.20

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.011

Sift

Benign

0.63

Sift4G

Benign

0.42

Polyphen

0.093

Vest4

0.063

MVP

0.17

MPC

0.45

ClinPred

0.016

GERP RS

-7.2

Varity_R

0.031

gMVP

0.35

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