Genetic Variant NM_001199206.4:c.235T>C (chr11-94306609-T-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001199206.4(IZUMO1R):c.235T>C(p.Cys79Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. C79G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

IZUMO1R
NM_001199206.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.73

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: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.994

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IZUMO1R	NM_001199206.4 link	c.235T>C	p.Cys79Arg	missense_variant	Exon 3 of 5	ENST00000687084.1	NP_001186135.1	A6ND01-1
IZUMO1R	NM_001393610.1 link	c.235T>C	p.Cys79Arg	missense_variant	Exon 2 of 4		NP_001380539.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IZUMO1R	ENST00000687084.1 link	c.235T>C	p.Cys79Arg	missense_variant	Exon 3 of 5		NM_001199206.4	ENSP00000510041.1	A6ND01-1
IZUMO1R	ENST00000328458.6 link	c.235T>C	p.Cys79Arg	missense_variant	Exon 2 of 4	5		ENSP00000332963.5	A6ND01-1
IZUMO1R	ENST00000440961.6 link	c.235T>C	p.Cys79Arg	missense_variant	Exon 2 of 4	5		ENSP00000416935.2	A6ND01-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

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:

0.00000402

AC:

AN:

248730

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:

0.00000889

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461702

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727136

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111860

Other (OTH)

AF:

0.00

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41444

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000826

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

D;.

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.68

T;T

M_CAP

Pathogenic

0.30

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.91

MutationAssessor

Pathogenic

3.6

H;H

PhyloP100

7.7

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-12

.;D

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

.;D

Sift4G

Uncertain

0.0020

.;D

Polyphen

1.0

.;D

Vest4

0.99

MutPred

0.93

Loss of helix (P = 0.0626);Loss of helix (P = 0.0626);

MVP

0.75

MPC

0.20

ClinPred

1.0

GERP RS

4.8

Varity_R

0.88

gMVP

0.97

Mutation Taster

=3/97

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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NM_001199206.4:c.235T>C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over