Genetic Variant IZUMO4:p.Asp58Tyr (chr19-2097117-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001039846.2(IZUMO4):c.172G>T(p.Asp58Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000253 in 1,460,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

IZUMO4
NM_001039846.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.960

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05274555).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IZUMO4	NM_001039846.2 link	c.172G>T	p.Asp58Tyr	missense_variant	Exon 1 of 10	ENST00000395301.8	NP_001034935.1	Q1ZYL8-1
IZUMO4	NM_001031735.3 link	c.172G>T	p.Asp58Tyr	missense_variant	Exon 1 of 9		NP_001026905.2	Q1ZYL8-2
IZUMO4	NM_001363588.2 link	c.172G>T	p.Asp58Tyr	missense_variant	Exon 1 of 8		NP_001350517.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IZUMO4	ENST00000395301.8 link	c.172G>T	p.Asp58Tyr	missense_variant	Exon 1 of 10	1	NM_001039846.2	ENSP00000378712.3		Q1ZYL8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000442

AC:

AN:

249066

Hom.:

AF XY:

0.0000814

AC XY:

AN XY:

135218

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 SAS exome

AF:

0.000360

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000253

AC:

AN:

1460238

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

726428

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000406

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000577

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 11, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.172G>T (p.D58Y) alteration is located in exon 1 (coding exon 1) of the IZUMO4 gene. This alteration results from a G to T substitution at nucleotide position 172, causing the aspartic acid (D) at amino acid position 58 to be replaced by a tyrosine (Y). 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

0.15

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.041

T;.;.;T;.

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.059

LIST_S2

Benign

0.84

T;T;T;T;T

M_CAP

Benign

0.028

MetaRNN

Benign

0.053

T;T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.34

N;N;.;.;.

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-2.5

D;.;.;D;.

REVEL

Benign

0.054

Sift

Benign

0.032

D;.;.;D;.

Sift4G

Uncertain

0.043

D;D;D;D;T

Polyphen

0.20

B;.;.;.;.

Vest4

0.24

MutPred

0.25

Loss of disorder (P = 0.0165);Loss of disorder (P = 0.0165);Loss of disorder (P = 0.0165);Loss of disorder (P = 0.0165);.;

MVP

0.10

MPC

0.57

ClinPred

0.15

GERP RS

0.55

Varity_R

0.17

gMVP

0.40

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

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