19-2097072-G-T

Variant names:

• chr19-2097072-G-T
• rs759722563
• NM_001039846.2:c.127G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001039846.2(IZUMO4):​c.127G>T​(p.Val43Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,532 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. V43M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: IZUMO4 NM_001039846.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.960
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16446748).

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.127G>T	p.Val43Leu	missense	Exon 1 of 10	NP_001034935.1	Q1ZYL8-1
	IZUMO4	NM_001031735.3		c.127G>T	p.Val43Leu	missense	Exon 1 of 9	NP_001026905.2	Q1ZYL8-2
	IZUMO4	NM_001363588.2		c.127G>T	p.Val43Leu	missense	Exon 1 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.127G>T	p.Val43Leu	missense	Exon 1 of 10	ENSP00000378712.3	Q1ZYL8-1
	IZUMO4	ENST00000395307.7	TSL:1	c.127G>T	p.Val43Leu	missense	Exon 1 of 9	ENSP00000378718.2	Q1ZYL8-2
	IZUMO4	ENST00000395296.5	TSL:2	c.127G>T	p.Val43Leu	missense	Exon 1 of 8	ENSP00000378709.2	A0A0A0MS61

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249378 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460532 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726552

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52194

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111926

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.019	T
Eigen	Benign	0.025
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.96
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.097
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.75	P
Vest4		0.38
MutPred		0.24		Loss of sheet (P = 0.0357)
MVP		0.20
MPC		0.12
ClinPred		0.42	T
GERP RS		3.2
PromoterAI		-0.0082	Neutral
Varity_R		0.41
gMVP		0.30
Mutation Taster		=93/7	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: rs759722563; hg19: chr19-2097071;