Genetic Variant NM_152510.4:c.398T>C (chr22-30119035-T-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 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. Variant has been reported in ClinVar as Uncertain significance (★).

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

Publications

0 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.77

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152510.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HORMAD2	NM_152510.4	MANE Select	c.398T>C	p.Met133Thr	missense	Exon 8 of 11	NP_689723.1	Q8N7B1
HORMAD2	NM_001329457.2		c.398T>C	p.Met133Thr	missense	Exon 9 of 12	NP_001316386.1	Q8N7B1
HORMAD2	NM_001329458.2		c.134T>C	p.Met45Thr	missense	Exon 7 of 10	NP_001316387.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HORMAD2	ENST00000336726.11	TSL:1 MANE Select	c.398T>C	p.Met133Thr	missense	Exon 8 of 11	ENSP00000336984.6	Q8N7B1
HORMAD2	ENST00000403975.1	TSL:2	c.398T>C	p.Met133Thr	missense	Exon 8 of 11	ENSP00000385055.1	Q8N7B1
HORMAD2	ENST00000862797.1		c.350T>C	p.Met117Thr	missense	Exon 6 of 9	ENSP00000532856.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

204730

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000140

AC:

AN:

1430510

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

708898

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32910

American (AMR)

AF:

0.00

AC:

AN:

40392

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25524

East Asian (EAS)

AF:

0.00

AC:

AN:

38972

South Asian (SAS)

AF:

0.00

AC:

AN:

81830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51674

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5672

European-Non Finnish (NFE)

AF:

9.14e-7

AC:

AN:

1094260

Other (OTH)

AF:

0.0000169

AC:

AN:

59276

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Uncertain

0.077

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.082

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.64

M_CAP

Benign

0.036

MetaRNN

Pathogenic

0.77

MetaSVM

Benign

-0.70

MutationAssessor

Pathogenic

3.0

PhyloP100

6.1

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.6

REVEL

Uncertain

0.31

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.0090

Polyphen

0.99

Vest4

0.86

MutPred

0.54

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

Mutation Taster

=54/46

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over