3-49256258-T-G

Position:

• chr3-49256258-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001135197.2(IHO1):​c.761T>G​(p.Leu254Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: IHO1 NM_001135197.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.00

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.761

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IHO1	NM_001135197.2	c.761T>G	p.Leu254Arg	missense_variant	8/8	ENST00000452691.7	NP_001128669.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IHO1	ENST00000452691.7	c.761T>G	p.Leu254Arg	missense_variant	8/8	2	NM_001135197.2	ENSP00000407837.2
IHO1	ENST00000296449.9	c.761T>G	p.Leu254Arg	missense_variant	10/10	1		ENSP00000296449.5
IHO1	ENST00000438782.5	c.761T>G	p.Leu254Arg	missense_variant	8/8	5		ENSP00000391788.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 16, 2023

The c.761T>G (p.L254R) alteration is located in exon 10 (coding exon 7) of the CCDC36 gene. This alteration results from a T to G substitution at nucleotide position 761, causing the leucine (L) at amino acid position 254 to be replaced by an arginine (R). 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	0.33
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;T;T
Eigen	Benign	0.18
Eigen_PC	Benign	0.087
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.68	.;T;.
M_CAP	Benign	0.011	T
MetaRNN	Pathogenic	0.76	D;D;D
MetaSVM	Benign	-1.1	T
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-4.9	D;D;D
REVEL	Benign	0.27
Sift	Benign	0.048	D;D;D
Sift4G	Benign	0.14	T;T;T
Polyphen		1.0	D;D;D
Vest4		0.89
MutPred		0.46		Gain of methylation at L254 (P = 0.0224);Gain of methylation at L254 (P = 0.0224);Gain of methylation at L254 (P = 0.0224);
MVP		0.87
MPC		1.0
ClinPred		0.94	D
GERP RS		5.0
Varity_R		0.59
gMVP		0.54

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-49293691;