rs34305723

Variant names:

• chr22-30098858-G-C
• rs34305723
• NM_152510.4:c.58G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_152510.4(HORMAD2):​c.58G>C​(p.Val20Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0028 in 1,608,456 control chromosomes in the GnomAD database, including 107 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (59 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (48 hom.)
• Consequence: HORMAD2 NM_152510.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.407
• Publications: 3 publications found

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001239866).
• BP6: Variant 22-30098858-G-C is Benign according to our data. Variant chr22-30098858-G-C is described in ClinVar as Benign. ClinVar VariationId is 788932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0538 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HORMAD2	NM_152510.4	MANE Select	c.58G>C	p.Val20Leu	missense	Exon 3 of 11	NP_689723.1	Q8N7B1
	HORMAD2	NM_001329457.2		c.58G>C	p.Val20Leu	missense	Exon 4 of 12	NP_001316386.1	Q8N7B1
	HORMAD2	NM_001329458.2		c.-170G>C		5_prime_UTR	Exon 3 of 10	NP_001316387.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HORMAD2	ENST00000336726.11	TSL:1 MANE Select	c.58G>C	p.Val20Leu	missense	Exon 3 of 11	ENSP00000336984.6	Q8N7B1
	HORMAD2	ENST00000403975.1	TSL:2	c.58G>C	p.Val20Leu	missense	Exon 3 of 11	ENSP00000385055.1	Q8N7B1
	HORMAD2	ENST00000862797.1		c.58G>C	p.Val20Leu	missense	Exon 3 of 9	ENSP00000532856.1

Frequencies

GnomAD3 genomes AF: 0.0148 AC: 2255 AN: 152128 Hom.: 59 Cov.: 32

Gnomad AFR AF: 0.0518

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00491

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00370 AC: 905 AN: 244694 AF XY: 0.00292

Gnomad AFR exome AF: 0.0526

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000188

Gnomad OTH exome AF: 0.00252

GnomAD4 exome AF: 0.00154 AC: 2241 AN: 1456210 Hom.: 48 Cov.: 30 AF XY: 0.00137 AC XY: 993 AN XY: 724330

African (AFR) AF: 0.0559 AC: 1856 AN: 33184

American (AMR) AF: 0.00224 AC: 98 AN: 43662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25916

East Asian (EAS) AF: 0.00 AC: 0 AN: 39576

South Asian (SAS) AF: 0.0000941 AC: 8 AN: 85028

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53244

Middle Eastern (MID) AF: 0.00175 AC: 10 AN: 5724

European-Non Finnish (NFE) AF: 0.0000991 AC: 110 AN: 1109758

Other (OTH) AF: 0.00264 AC: 159 AN: 60118

GnomAD4 genome AF: 0.0148 AC: 2260 AN: 152246 Hom.: 59 Cov.: 32 AF XY: 0.0145 AC XY: 1078 AN XY: 74438

African (AFR) AF: 0.0518 AC: 2151 AN: 41542

American (AMR) AF: 0.00491 AC: 75 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68014

Other (OTH) AF: 0.00993 AC: 21 AN: 2114

Alfa AF: 0.00230 Hom.: 2

Bravo AF: 0.0170

ESP6500AA AF: 0.0487 AC: 178

ESP6500EA AF: 0.000123 AC: 1

ExAC AF: 0.00459 AC: 554

Asia WGS AF: 0.00347 AC: 12 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	8.1
DANN	Benign	0.87
DEOGEN2	Benign	0.0029	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.21	N
PhyloP100		-0.41
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.048
Sift	Benign	0.51	T
Sift4G	Benign	0.43	T
Polyphen		0.0	B
Vest4		0.17
MVP		0.067
MPC		0.052
ClinPred		0.0021	T
GERP RS		-4.2
Varity_R		0.041
gMVP		0.39
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs34305723; hg19: chr22-30494847; COSMIC: COSV60898101;