19-2097949-C-T

Variant names:

• chr19-2097949-C-T
• rs147322963
• NM_001039846.2:c.391C>T

Variant summary

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

The NM_001039846.2(IZUMO4):​c.391C>T​(p.Arg131Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000722 in 1,613,196 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/15 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R131S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00074 (1 hom.)
• Consequence: IZUMO4 NM_001039846.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.72
• Publications: 5 publications found

Genes affected

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0074129105).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IZUMO4	NM_001039846.2	MANE Select	c.391C>T	p.Arg131Cys	missense	Exon 4 of 10	NP_001034935.1	Q1ZYL8-1
	IZUMO4	NM_001031735.3		c.391C>T	p.Arg131Cys	missense	Exon 4 of 9	NP_001026905.2	Q1ZYL8-2
	IZUMO4	NM_001363588.2		c.391C>T	p.Arg131Cys	missense	Exon 4 of 8	NP_001350517.1	A0A0A0MS61

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IZUMO4	ENST00000395301.8	TSL:1 MANE Select	c.391C>T	p.Arg131Cys	missense	Exon 4 of 10	ENSP00000378712.3	Q1ZYL8-1
	IZUMO4	ENST00000395307.7	TSL:1	c.391C>T	p.Arg131Cys	missense	Exon 4 of 9	ENSP00000378718.2	Q1ZYL8-2
	IZUMO4	ENST00000395296.5	TSL:2	c.391C>T	p.Arg131Cys	missense	Exon 4 of 8	ENSP00000378709.2	A0A0A0MS61

Frequencies

GnomAD3 genomes AF: 0.000578 AC: 88 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000941

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000889 AC: 223 AN: 250890 AF XY: 0.000796

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.000579

Gnomad ASJ exome AF: 0.00577

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00109

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.000737 AC: 1076 AN: 1460850 Hom.: 1 Cov.: 33 AF XY: 0.000674 AC XY: 490 AN XY: 726746

African (AFR) AF: 0.000119 AC: 4 AN: 33478

American (AMR) AF: 0.000514 AC: 23 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00582 AC: 152 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86250

European-Finnish (FIN) AF: 0.000114 AC: 6 AN: 52466

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.000736 AC: 818 AN: 1111960

Other (OTH) AF: 0.00103 AC: 62 AN: 60384

GnomAD4 genome AF: 0.000578 AC: 88 AN: 152346 Hom.: 0 Cov.: 33 AF XY: 0.000564 AC XY: 42 AN XY: 74500

African (AFR) AF: 0.0000962 AC: 4 AN: 41582

American (AMR) AF: 0.000131 AC: 2 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000941 AC: 64 AN: 68022

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00108 Hom.: 0

Bravo AF: 0.000774

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.000832 AC: 101

EpiCase AF: 0.000927

EpiControl AF: 0.00148

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.49
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.0074	T
PhyloP100		1.7
Sift4G	Benign	0.24	T
Vest4		0.18
MVP		0.15
ClinPred		0.017	T
GERP RS		2.7
Varity_R		0.22
Mutation Taster		=77/23	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: rs147322963; hg19: chr19-2097948;