dbSNP rs374968054: IZUMO1R:p.Glu40Lys (chr11-94305754-G-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001199206.4(IZUMO1R):c.118G>A(p.Glu40Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,613,262 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

IZUMO1R
NM_001199206.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.56

Publications

0 publications found

Variant links:

Genes affected

IZUMO1R (HGNC:32565): (IZUMO1 receptor, JUNO) Enables signaling receptor activity. Predicted to be involved in cell adhesion; fusion of sperm to egg plasma membrane involved in single fertilization; and sperm-egg recognition. Predicted to be located in extracellular region and plasma membrane. Predicted to be anchored component of external side of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

IZUMO1R links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.862

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IZUMO1R	NM_001199206.4 link	c.118G>A	p.Glu40Lys	missense_variant	Exon 2 of 5	ENST00000687084.1	NP_001186135.1	A6ND01-1
IZUMO1R	NM_001393610.1 link	c.118G>A	p.Glu40Lys	missense_variant	Exon 1 of 4		NP_001380539.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IZUMO1R	ENST00000687084.1 link	c.118G>A	p.Glu40Lys	missense_variant	Exon 2 of 5		NM_001199206.4	ENSP00000510041.1	A6ND01-1
IZUMO1R	ENST00000328458.6 link	c.118G>A	p.Glu40Lys	missense_variant	Exon 1 of 4	5		ENSP00000332963.5	A6ND01-1
IZUMO1R	ENST00000440961.6 link	c.118G>A	p.Glu40Lys	missense_variant	Exon 1 of 4	5		ENSP00000416935.2	A6ND01-2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151684

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000804

AC:

AN:

248654

AF XY:

0.00000741

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000411

AC:

AN:

1461578

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

727080

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0000495

AC:

AN:

1111792

Other (OTH)

AF:

0.0000828

AC:

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151684

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74046

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41290

American (AMR)

AF:

0.00

AC:

AN:

15184

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5140

South Asian (SAS)

AF:

0.00

AC:

AN:

4768

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67946

Other (OTH)

AF:

0.00

AC:

AN:

2076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000119

AC:

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 31, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.118G>A (p.E40K) alteration is located in exon 1 (coding exon 1) of the IZUMO1R gene. This alteration results from a G to A substitution at nucleotide position 118, causing the glutamic acid (E) at amino acid position 40 to be replaced by a lysine (K). 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

Uncertain

0.38

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

D;.

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

D;D

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.86

D;D

MetaSVM

Uncertain

0.47

MutationAssessor

Pathogenic

3.6

H;H

PhyloP100

8.6

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.8

N;D

REVEL

Uncertain

0.64

Sift

Uncertain

0.0050

D;D

Sift4G

Uncertain

0.0040

.;D

Polyphen

1.0

.;D

Vest4

0.92

MVP

0.49

MPC

0.18

ClinPred

1.0

GERP RS

4.7

PromoterAI

-0.029

Neutral

(source)

Varity_R

0.81

gMVP

0.92

Mutation Taster

=64/36

polymorphism

(source)

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

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

rs374968054

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over