Genetic Variant IZUMO1R:p.Asp142Val (chr11-94307241-A-T) – 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.425A>T(p.Asp142Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,456,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D142A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

IZUMO1R
NM_001199206.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.82

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:

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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, 0.859

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IZUMO1R	NM_001199206.4 link	c.425A>T	p.Asp142Val	missense_variant	Exon 4 of 5	ENST00000687084.1	NP_001186135.1	A6ND01-1
IZUMO1R	NM_001393610.1 link	c.425A>T	p.Asp142Val	missense_variant	Exon 3 of 4		NP_001380539.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IZUMO1R	ENST00000687084.1 link	c.425A>T	p.Asp142Val	missense_variant	Exon 4 of 5		NM_001199206.4	ENSP00000510041.1	A6ND01-1
IZUMO1R	ENST00000328458.6 link	c.425A>T	p.Asp142Val	missense_variant	Exon 3 of 4	5		ENSP00000332963.5	A6ND01-1
IZUMO1R	ENST00000440961.6 link	c.404A>T	p.Asp135Val	missense_variant	Exon 3 of 4	5		ENSP00000416935.2	A6ND01-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1456958

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

AN XY:

724178

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33448

American (AMR)

AF:

0.00

AC:

AN:

43828

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26022

East Asian (EAS)

AF:

0.00

AC:

AN:

39520

South Asian (SAS)

AF:

0.00

AC:

AN:

85056

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53178

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1109910

Other (OTH)

AF:

0.0000166

AC:

AN:

60236

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.38

T;.

Eigen

Benign

0.18

Eigen_PC

Benign

0.14

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Benign

0.050

MetaRNN

Pathogenic

0.86

D;D

MetaSVM

Benign

-0.39

MutationAssessor

Pathogenic

3.4

M;.

PhyloP100

6.8

PrimateAI

Benign

0.43

PROVEAN

Pathogenic

-7.6

.;D

REVEL

Pathogenic

0.72

Sift

Uncertain

0.011

.;D

Sift4G

Uncertain

0.035

.;D

Polyphen

0.99

.;D

Vest4

0.92

MutPred

0.66

.;Gain of MoRF binding (P = 0.0422);

MVP

0.68

MPC

0.18

ClinPred

0.99

GERP RS

3.5

Varity_R

0.20

gMVP

0.95

Mutation Taster

=32/68

disease causing

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over