22-30119035-T-C

Variant names:

• chr22-30119035-T-C
• rs1234284195
• NM_152510.4:c.398T>C

Variant summary

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

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.12

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]

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, 0.77

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HORMAD2	NM_152510.4	c.398T>C	p.Met133Thr	missense_variant	Exon 8 of 11	ENST00000336726.11	NP_689723.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HORMAD2	ENST00000336726.11	c.398T>C	p.Met133Thr	missense_variant	Exon 8 of 11	1	NM_152510.4	ENSP00000336984.6
HORMAD2	ENST00000403975.1	c.398T>C	p.Met133Thr	missense_variant	Exon 8 of 11	2		ENSP00000385055.1
HORMAD2	ENST00000450612.5	n.*85T>C		non_coding_transcript_exon_variant	Exon 7 of 9	5		ENSP00000393415.1
HORMAD2	ENST00000450612.5	n.*85T>C		3_prime_UTR_variant	Exon 7 of 9	5		ENSP00000393415.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1430510 Hom.: 0 Cov.: 27 AF XY: 0.00000141 AC XY: 1 AN XY: 708898

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.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.082	T;T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.64	.;T
M_CAP	Benign	0.036	D
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Benign	-0.70	T
MutationAssessor	Pathogenic	3.0	M;M
PrimateAI	Uncertain	0.52	T
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	D
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

Other links and lift over

dbSNP: rs1234284195; hg19: chr22-30515024;