rs147392516

Variant names:

• chr1-91316470-G-A
• rs147392516
• NM_001017975.6:c.2819C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001017975.6(HFM1):​c.2819C>T​(p.Thr940Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000116 in 1,463,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T940A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000099 (0 hom.)
• Consequence: HFM1 NM_001017975.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.55
• Publications: 2 publications found

Genes affected

HFM1 (HGNC:20193): (helicase for meiosis 1) 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]

HFM1 Gene-Disease associations (from GenCC):

• premature ovarian failure 9

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• male infertility with azoospermia or oligozoospermia due to single gene mutation

  Inheritance: AR Classification: NO_KNOWN Submitted by: King Faisal Specialist Hospital and Research Center

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.102594465).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001017975.6. 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
	HFM1	NM_001017975.6	MANE Select	c.2819C>T	p.Thr940Ile	missense	Exon 26 of 39	NP_001017975.5	A2PYH4-1
	HFM1	NR_165455.1		n.2489-286C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HFM1	ENST00000370425.8	TSL:1 MANE Select	c.2819C>T	p.Thr940Ile	missense	Exon 26 of 39	ENSP00000359454.3	A2PYH4-1
	HFM1	ENST00000430465.1	TSL:1	c.452C>T	p.Thr151Ile	missense	Exon 7 of 19	ENSP00000387661.1	H0Y3X7
	HFM1	ENST00000462405.5	TSL:2	n.745C>T		non_coding_transcript_exon	Exon 9 of 21

Frequencies

GnomAD3 genomes AF: 0.0000264 AC: 4 AN: 151730 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000726

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000484 AC: 1 AN: 206426 AF XY: 0.00

Gnomad AFR exome AF: 0.0000744

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: 0.00000991 AC: 13 AN: 1311448 Hom.: 0 Cov.: 21 AF XY: 0.00000613 AC XY: 4 AN XY: 653024

African (AFR) AF: 0.000347 AC: 10 AN: 28834

American (AMR) AF: 0.00 AC: 0 AN: 32110

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23350

East Asian (EAS) AF: 0.00 AC: 0 AN: 35672

South Asian (SAS) AF: 0.00 AC: 0 AN: 65266

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50540

Middle Eastern (MID) AF: 0.000186 AC: 1 AN: 5368

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1015838

Other (OTH) AF: 0.0000367 AC: 2 AN: 54470

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 151848 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74194

African (AFR) AF: 0.0000724 AC: 3 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10472

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67932

Other (OTH) AF: 0.00 AC: 0 AN: 2102

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.013	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.6	L
PhyloP100		5.6
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.082
Sift	Benign	0.27	T
Sift4G	Benign	0.18	T
Polyphen		0.098	B
Vest4		0.25
MVP		0.39
MPC		0.11
ClinPred		0.29	T
GERP RS		5.1
Varity_R		0.24
gMVP		0.29
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs147392516; hg19: chr1-91782027;