HFM1

protein-coding

helicase for meiosis 1, the group of RNA helicases

Gene summary

The protein encoded by this gene is thought to be an ATP-dependent DNA helicase and is expressed mainly in germ-line cells. Defects in this gene are a cause of premature ovarian failure 9 (POF9). [provided by RefSeq, Apr 2014]

Previous symbols:

SEC63D1

MANE transcript

NM_001017975.6

Inheritance

AR, AD

ClinVar variants

P:21U:194B:30

Top phenotype

Premature ovarian failure 9

gnomAD constraint

pLI —, LoF o/e 0.75

Max pathogenic AF

—

Genomic locus

chr1:91,260,766-91,404,856

External References & Databases

Ensembl (ENSG00000162669)

Transcript & Mutation Effects

hg38 • Region Span ~144.1 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

male infertility with azoospermia or oligozoospermia due to single gene mutationNO_KNOWN

Inheritance Pattern: AR

Disease ID:MONDO:0018393

Submitter: King Faisal Specialist Hospital and Research Center

Convincing evidence disputing a role for this gene is this disease has arisen since the initial report identifying an association between the gene and disease. Alhathal et al., 2020 (PMID: 32719396) reported a LOF variant in a large male infertility cohort (n=285 infertile man and case–control fertile man).

premature ovarian failure 9STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014322

Submitter: PanelApp Australia

premature ovarian failure 9LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0014322

Submitter: PanelApp Australia

premature ovarian failure 9LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0014322

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Premature ovarian failure 9AR

Manifestation: Endocrine; Obstetric

Intervention: Obstetric

Rationale: Genetic knowledge may be beneficial to allow interventions such as preserving eggs in women with premature ovarian insufficiency

Refs: 24597873

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HFM1 variants in ClinVar

7 Conditions Cataloged

not specifiedTotal: 197

Premature ovarian failure 9Total: 21

HFM1-related disorderTotal: 16

not providedTotal: 14

Spermatogenic failure 4Total: 2

Genetic non-acquired premature ovarian failureTotal: 2

AzoospermiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001017975.6. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			3 clinvar	9 clinvar	2 clinvar	14
missense	5 clinvar	1 clinvar	183 clinvar	17 clinvar	2 clinvar	208
nonsense	1 clinvar	4 clinvar	1 clinvar			6
start loss		1 clinvar				1
frameshift	1 clinvar	4 clinvar	4 clinvar			9
splice donor/acceptor (+/-2bp)	2 clinvar	2 clinvar	3 clinvar			7
Total	9	12	194	26	4	245

Highest pathogenic variant AF is 0.0000751985

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 27 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001017975.6	RefSeq	NP_001017975.5	38	MANE Select
ENST00000370425.8	Ensembl	ENSP00000359454.3	38	MANE Select
ENST00000427444.1	Ensembl	ENSP00000388900.1	3	Standard
ENST00000430465.1	Ensembl	ENSP00000387661.1	19	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

resolution of meiotic recombination intermediates

Molecular Function

nucleic acid binding
helicase activity
ATP binding

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000370425
Coding exons: 38
Length: 144104
Individuals with no LoFs: 125603
Homozygous LoFs: 0
Heterozygous LoFs: 137
Defined: 125740
p: 0.000545

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.742	627	682	0.920	0.0000319	9464
Missense (PolyPhen)		142	181.84	0.78089		2547
Synonymous	0.593	215	226	0.950	0.0000105	2551
Loss of Function	2.07	60	80.0	0.750	0.00000415	1083

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00032	0.00031	rare
Latino/Admixed American	0.00045	0.00040	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00064	0.00060	rare
Finnish	0.00070	0.00069	rare
European (Non-Finnish)	0.00073	0.00070	rare
South Asian	0.00041	0.00039	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Required for crossover formation and complete synapsis of homologous chromosomes during meiosis. {ECO:0000250|UniProtKB:D3Z4R1}.;

Intolerance Scores

LoFtool: 0.986
RVIS EVS: -0.72
RVIS percentile EVS: 14.27

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.177

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium