Variant 22-30119035-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_152510.4(HORMAD2):c.398T>C(p.Met133Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000014 in 1,430,510 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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: 0.0000014 ( 0 hom. )

Consequence

HORMAD2
NM_152510.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.12

Variant links:

Genes affected

HORMAD2 (HGNC:28383): (HORMA domain containing 2) Predicted to be involved in meiotic sister chromatid cohesion. Located in centrosome; cytosol; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

HORMAD2 links:

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ACMG classification

Classification made for transcript

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, 0.77

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HORMAD2	NM_152510.4 linkuse as main transcript	c.398T>C	p.Met133Thr	missense_variant	8/11	ENST00000336726.11	NP_689723.1	Q8N7B1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HORMAD2	ENST00000336726.11 linkuse as main transcript	c.398T>C	p.Met133Thr	missense_variant	8/11	1	NM_152510.4	ENSP00000336984.6	Q8N7B1
HORMAD2	ENST00000403975.1 linkuse as main transcript	c.398T>C	p.Met133Thr	missense_variant	8/11	2		ENSP00000385055.1	Q8N7B1
HORMAD2	ENST00000450612.5 linkuse as main transcript	n.*85T>C		non_coding_transcript_exon_variant	7/9	5		ENSP00000393415.1	F8WES9
HORMAD2	ENST00000450612.5 linkuse as main transcript	n.*85T>C		3_prime_UTR_variant	7/9	5		ENSP00000393415.1	F8WES9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000140

AC:

AN:

1430510

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

708898

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.14e-7

Gnomad4 OTH exome

AF:

0.0000169

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 05, 2024

The c.398T>C (p.M133T) alteration is located in exon 8 (coding exon 7) of the HORMAD2 gene. This alteration results from a T to C substitution at nucleotide position 398, causing the methionine (M) at amino acid position 133 to be replaced by a threonine (T). 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

Uncertain

0.39

BayesDel_addAF

Uncertain

0.077

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.082

T;T

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.64

.;T

M_CAP

Benign

0.036

MetaRNN

Pathogenic

0.77

D;D

MetaSVM

Benign

-0.70

MutationAssessor

Pathogenic

3.0

M;M

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.6

D;D

REVEL

Uncertain

0.31

Sift

Uncertain

0.0070

D;D

Sift4G

Uncertain

0.0090

D;D

Polyphen

0.99

D;D

Vest4

0.86

MutPred

0.54

Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);

MVP

0.45

MPC

0.36

ClinPred

0.99

GERP RS

4.8

Varity_R

0.70

gMVP

0.47

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over