chr19-48743609-A-T

Variant names:

• chr19-48743609-A-T
• rs838147
• NM_182575.3:c.419-84T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_182575.3(IZUMO1):​c.419-84T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000225 in 889,524 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: IZUMO1 NM_182575.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.323
• Publications: 43 publications found

Genes affected

IZUMO1 (HGNC:28539): (izumo sperm-oocyte fusion 1) The sperm-specific protein Izumo, named for a Japanese shrine dedicated to marriage, is essential for sperm-egg plasma membrane binding and fusion (Inoue et al., 2005 [PubMed 15759005]).[supplied by OMIM, Mar 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182575.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IZUMO1	NM_182575.3	MANE Select	c.419-84T>A		intron	N/A	NP_872381.2
	IZUMO1	NM_001321864.1		c.80-84T>A		intron	N/A	NP_001308793.1
	IZUMO1	NM_001321865.1		c.-141-84T>A		intron	N/A	NP_001308794.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IZUMO1	ENST00000332955.7	TSL:1 MANE Select	c.419-84T>A		intron	N/A	ENSP00000327786.2
	IZUMO1	ENST00000595517.5	TSL:1	n.*145-84T>A		intron	N/A	ENSP00000471815.1
	IZUMO1	ENST00000595937.5	TSL:1	n.419-84T>A		intron	N/A	ENSP00000470144.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000225 AC: 2 AN: 889524 Hom.: 0 Cov.: 12 AF XY: 0.00 AC XY: 0 AN XY: 463240

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 22284

American (AMR) AF: 0.00 AC: 0 AN: 39276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22238

East Asian (EAS) AF: 0.0000277 AC: 1 AN: 36134

South Asian (SAS) AF: 0.00 AC: 0 AN: 72914

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50838

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4684

European-Non Finnish (NFE) AF: 0.00000167 AC: 1 AN: 599732

Other (OTH) AF: 0.00 AC: 0 AN: 41424

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.6
DANN	Benign	0.74
PhyloP100		-0.32

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: rs838147; hg19: chr19-49246866;