19-2098292-C-T

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

4
15

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]

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
IZUMO4NM_001039846.2 linkc.479C>T p.Ser160Leu missense_variant Exon 6 of 10 ENST00000395301.8 NP_001034935.1 Q1ZYL8-1
IZUMO4NM_001031735.3 linkc.479C>T p.Ser160Leu missense_variant Exon 6 of 9 NP_001026905.2 Q1ZYL8-2
IZUMO4NM_001363588.2 linkc.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
IZUMO4ENST00000395301.8 linkc.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:
51
AN:
152200
Hom.:
0
Cov.:
33
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.:
0
AF XY:
0.000596
AC XY:
81
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.:
2
Cov.:
34
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:
51
AN:
152200
Hom.:
0
Cov.:
33
AF XY:
0.000282
AC XY:
21
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.:
0
Bravo
AF:
0.000317
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000581
AC:
5
ExAC
AF:
0.000445
AC:
54
Asia WGS
AF:
0.00115
AC:
4
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
T
BayesDel_noAF
Benign
-0.38
CADD
Uncertain
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.12
T;.;.;T;.
Eigen
Benign
-0.11
Eigen_PC
Benign
-0.26
FATHMM_MKL
Benign
0.23
N
LIST_S2
Benign
0.83
T;T;T;T;T
M_CAP
Benign
0.027
D
MetaRNN
Benign
0.042
T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.90
L;L;.;.;.
PrimateAI
Benign
0.42
T
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
T
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.

Other links and lift over

dbSNP: rs139812380; hg19: chr19-2098291; COSMIC: COSV61433387; COSMIC: COSV61433387; API