22-30122122-G-T

Position:

• chr22-30122122-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_152510.4(HORMAD2):​c.727G>T​(p.Asp243Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,434 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign 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: 0.728

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30147067).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HORMAD2	NM_152510.4	c.727G>T	p.Asp243Tyr	missense_variant	10/11	ENST00000336726.11	NP_689723.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HORMAD2	ENST00000336726.11	c.727G>T	p.Asp243Tyr	missense_variant	10/11	1	NM_152510.4	ENSP00000336984	P1
HORMAD2	ENST00000403975.1	c.727G>T	p.Asp243Tyr	missense_variant	10/11	2		ENSP00000385055	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461434 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726968

Gnomad4 AFR exome AF: 0.0000597

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Nov 15, 2023

The c.727G>T (p.D243Y) alteration is located in exon 10 (coding exon 9) of the HORMAD2 gene. This alteration results from a G to T substitution at nucleotide position 727, causing the aspartic acid (D) at amino acid position 243 to be replaced by a tyrosine (Y). 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	0.10
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T;T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.73	.;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.5	N;N
REVEL	Benign	0.12
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.033	D;D
Polyphen		0.98	D;D
Vest4		0.35
MutPred		0.46		Loss of ubiquitination at K240 (P = 0.051);Loss of ubiquitination at K240 (P = 0.051);
MVP		0.53
MPC		0.25
ClinPred		0.52	D
GERP RS		2.7
Varity_R		0.10
gMVP		0.36

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: rs1922494344; hg19: chr22-30518111;