chr11-94305746-C-T

Variant names:

• chr11-94305746-C-T
• rs943950966
• NM_001199206.4:c.110C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001199206.4(IZUMO1R):​c.110C>T​(p.Pro37Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: IZUMO1R NM_001199206.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.79
• Publications: 0 publications found

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]

ACMG classification

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, 0.988

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IZUMO1R	NM_001199206.4	c.110C>T	p.Pro37Leu	missense_variant	Exon 2 of 5	ENST00000687084.1	NP_001186135.1
IZUMO1R	NM_001393610.1	c.110C>T	p.Pro37Leu	missense_variant	Exon 1 of 4		NP_001380539.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IZUMO1R	ENST00000687084.1	c.110C>T	p.Pro37Leu	missense_variant	Exon 2 of 5		NM_001199206.4	ENSP00000510041.1
IZUMO1R	ENST00000328458.6	c.110C>T	p.Pro37Leu	missense_variant	Exon 1 of 4	5		ENSP00000332963.5
IZUMO1R	ENST00000440961.6	c.110C>T	p.Pro37Leu	missense_variant	Exon 1 of 4	5		ENSP00000416935.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 18, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.110C>T (p.P37L) alteration is located in exon 1 (coding exon 1) of the IZUMO1R gene. This alteration results from a C to T substitution at nucleotide position 110, causing the proline (P) at amino acid position 37 to be replaced by a leucine (L). 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	0.50
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D;.
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Pathogenic	3.6	H;H
PhyloP100		6.8
PrimateAI	Benign	0.36	T
PROVEAN	Pathogenic	-9.6	.;D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0010	.;D
Polyphen		1.0	.;D
Vest4		0.93
MutPred		0.84		Loss of disorder (P = 0.0345);Loss of disorder (P = 0.0345);
MVP		0.45
MPC		0.18
ClinPred		1.0	D
GERP RS		4.7
PromoterAI		0.0092	Neutral
Varity_R		0.79
gMVP		0.89
Mutation Taster		=52/48	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: rs943950966; hg19: chr11-94038912;