Genetic Variant IZUMO4:p.Ala161Val (chr19-2098295-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001039846.2(IZUMO4):c.482C>T(p.Ala161Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000179 in 1,613,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

IZUMO4
NM_001039846.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.15

Publications

5 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008075923).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001039846.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IZUMO4	NM_001039846.2	MANE Select	c.482C>T	p.Ala161Val	missense	Exon 6 of 10	NP_001034935.1	Q1ZYL8-1
IZUMO4	NM_001031735.3		c.482C>T	p.Ala161Val	missense	Exon 6 of 9	NP_001026905.2	Q1ZYL8-2
IZUMO4	NM_001363588.2		c.482C>T	p.Ala161Val	missense	Exon 6 of 8	NP_001350517.1	A0A0A0MS61

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IZUMO4	ENST00000395301.8	TSL:1 MANE Select	c.482C>T	p.Ala161Val	missense	Exon 6 of 10	ENSP00000378712.3	Q1ZYL8-1
IZUMO4	ENST00000395307.7	TSL:1	c.482C>T	p.Ala161Val	missense	Exon 6 of 9	ENSP00000378718.2	Q1ZYL8-2
IZUMO4	ENST00000395296.5	TSL:2	c.482C>T	p.Ala161Val	missense	Exon 6 of 8	ENSP00000378709.2	A0A0A0MS61

Frequencies

GnomAD3 genomes

AF:

0.000283

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00433

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000235

AC:

AN:

251176

AF XY:

0.000236

show subpopulations

Gnomad AFR exome

AF:

0.000370

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00139

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000229

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000168

AC:

246

AN:

1461554

Hom.:

Cov.:

AF XY:

0.000173

AC XY:

126

AN XY:

727070

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33478

American (AMR)

AF:

0.0000894

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00230

AC:

AN:

26134

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.000185

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53142

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.000124

AC:

138

AN:

1111992

Other (OTH)

AF:

0.000265

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000282

AC:

AN:

152302

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41562

American (AMR)

AF:

0.000196

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00433

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000226

Hom.:

Bravo

AF:

0.000253

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000222

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000296

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.71

CADD

Benign

9.5

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.023

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.037

LIST_S2

Benign

0.42

M_CAP

Benign

0.0059

MetaRNN

Benign

0.0081

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

PhyloP100

-1.1

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.8

REVEL

Benign

0.0050

Sift

Benign

0.22

Sift4G

Benign

0.26

Polyphen

0.0090

Vest4

0.14

MVP

0.014

MPC

0.16

ClinPred

0.0064

GERP RS

-3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.033

gMVP

0.35

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over