3-49256498-C-T

Variant names:

• chr3-49256498-C-T
• rs537002321
• NM_001135197.2:c.1001C>T

Variant summary

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

The NM_001135197.2(IHO1):​c.1001C>T​(p.Ala334Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,614,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: IHO1 NM_001135197.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.698
• Publications: 0 publications found

Genes affected

IHO1 (HGNC:27945): (interactor of HORMAD1 1) Predicted to be involved in gamete generation; meiosis I cell cycle process; and regulation of homologous chromosome segregation. Predicted to be active in condensed nuclear chromosome. [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=0.101388305).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001135197.2. 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
	IHO1	NM_001135197.2	MANE Select	c.1001C>T	p.Ala334Val	missense	Exon 8 of 8	NP_001128669.1	Q8IYA8-1
	IHO1	NM_178173.4		c.1001C>T	p.Ala334Val	missense	Exon 10 of 10	NP_835467.2	Q8IYA8-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IHO1	ENST00000452691.7	TSL:2 MANE Select	c.1001C>T	p.Ala334Val	missense	Exon 8 of 8	ENSP00000407837.2	Q8IYA8-1
	IHO1	ENST00000296449.9	TSL:1	c.1001C>T	p.Ala334Val	missense	Exon 10 of 10	ENSP00000296449.5	Q8IYA8-1
	IHO1	ENST00000438782.5	TSL:5	c.1001C>T	p.Ala334Val	missense	Exon 8 of 8	ENSP00000391788.1	Q8IYA8-1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152148 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251426 AF XY: 0.0000294

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000465 AC: 68 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.0000468 AC XY: 34 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000585 AC: 65 AN: 1112012

Other (OTH) AF: 0.0000497 AC: 3 AN: 60396

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152148 Hom.: 0 Cov.: 31 AF XY: 0.0000942 AC XY: 7 AN XY: 74332

African (AFR) AF: 0.00 AC: 0 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000987 Hom.: 0

Bravo AF: 0.0000453

EpiCase AF: 0.000327

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	12
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.98	T
PhyloP100		0.70
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.032
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.041	D
Polyphen		0.48	P
Vest4		0.096
MVP		0.42
MPC		0.38
ClinPred		0.29	T
GERP RS		3.3
Varity_R		0.091
gMVP		0.11
Mutation Taster		=90/10	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: rs537002321; hg19: chr3-49293931;