Genetic Variant IZUMO4:p.Ser160Leu (chr19-2098292-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

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

The NM_001039846.2(IZUMO4):c.479C>T(p.Ser160Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000524 in 1,613,754 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00054 ( 2 hom. )

Consequence

IZUMO4
NM_001039846.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.63

Variant links:

Genes affected

IZUMO4 (HGNC:26950): (IZUMO family member 4) Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

IZUMO4 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=0.042238265).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IZUMO4	NM_001039846.2 link	c.479C>T	p.Ser160Leu	missense_variant	Exon 6 of 10	ENST00000395301.8	NP_001034935.1	Q1ZYL8-1
IZUMO4	NM_001031735.3 link	c.479C>T	p.Ser160Leu	missense_variant	Exon 6 of 9		NP_001026905.2	Q1ZYL8-2
IZUMO4	NM_001363588.2 link	c.479C>T	p.Ser160Leu	missense_variant	Exon 6 of 8		NP_001350517.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IZUMO4	ENST00000395301.8 link	c.479C>T	p.Ser160Leu	missense_variant	Exon 6 of 10	1	NM_001039846.2	ENSP00000378712.3		Q1ZYL8-1

Frequencies

GnomAD3 genomes

AF:

0.000335

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000510

AC:

128

AN:

251180

Hom.:

AF XY:

0.000596

AC XY:

AN XY:

135816

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.0000995

Gnomad EAS exome

AF:

0.00125

Gnomad SAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.000416

Gnomad NFE exome

AF:

0.000581

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000544

AC:

795

AN:

1461554

Hom.:

Cov.:

AF XY:

0.000549

AC XY:

399

AN XY:

727078

show subpopulations

Gnomad4 AFR exome

AF:

0.000388

Gnomad4 AMR exome

AF:

0.000291

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00111

Gnomad4 SAS exome

AF:

0.000359

Gnomad4 FIN exome

AF:

0.000339

Gnomad4 NFE exome

AF:

0.000588

Gnomad4 OTH exome

AF:

0.000315

GnomAD4 genome

AF:

0.000335

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.000393

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000565

Gnomad4 NFE

AF:

0.000397

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000431

Hom.:

Bravo

AF:

0.000317

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000445

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.479C>T (p.S160L) alteration is located in exon 6 (coding exon 6) of the IZUMO4 gene. This alteration results from a C to T substitution at nucleotide position 479, causing the serine (S) at amino acid position 160 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

Benign

0.20

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.38

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

T;.;.;T;.

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.83

T;T;T;T;T

M_CAP

Benign

0.027

MetaRNN

Benign

0.042

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

L;L;.;.;.

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-3.6

D;.;.;.;.

REVEL

Benign

0.17

Sift

Uncertain

0.0030

D;.;.;.;.

Sift4G

Uncertain

0.0080

D;D;D;D;D

Polyphen

1.0

D;.;.;.;.

Vest4

0.62

MVP

0.25

MPC

0.52

ClinPred

0.031

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.17

gMVP

0.72

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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