Genetic Variant HFM1:p.Ser1204Asn (chr1-91274787-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001017975.6(HFM1):c.3611G>A(p.Ser1204Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,571,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

HFM1
NM_001017975.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.350

Publications

0 publications found

Variant links:

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

HFM1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.024917305).

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.3611G>A	p.Ser1204Asn	missense	Exon 33 of 39	NP_001017975.5	A2PYH4-1
	HFM1	NR_165455.1		n.3201G>A		non_coding_transcript_exon	Exon 27 of 33

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HFM1	ENST00000370425.8	TSL:1 MANE Select	c.3611G>A	p.Ser1204Asn	missense	Exon 33 of 39	ENSP00000359454.3	A2PYH4-1
HFM1	ENST00000430465.1	TSL:1	c.1244G>A	p.Ser415Asn	missense	Exon 14 of 19	ENSP00000387661.1	H0Y3X7
HFM1	ENST00000462405.5	TSL:2	n.1537G>A		non_coding_transcript_exon	Exon 16 of 21

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000404

AC:

AN:

247600

AF XY:

0.0000373

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000798

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000240

AC:

AN:

1418970

Hom.:

Cov.:

AF XY:

0.0000254

AC XY:

AN XY:

708148

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32648

American (AMR)

AF:

0.0000454

AC:

AN:

44054

Ashkenazi Jewish (ASJ)

AF:

0.000775

AC:

AN:

25800

East Asian (EAS)

AF:

0.00

AC:

AN:

39348

South Asian (SAS)

AF:

0.00

AC:

AN:

83594

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53296

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5582

European-Non Finnish (NFE)

AF:

0.00000651

AC:

AN:

1075684

Other (OTH)

AF:

0.0000848

AC:

AN:

58964

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.410

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41430

American (AMR)

AF:

0.00

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.000864

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000900

Hom.:

Bravo

AF:

0.0000113

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000412

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.56

CADD

Benign

9.0

(source)

DANN

Benign

0.57

DEOGEN2

Benign

0.0063

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.53

M_CAP

Benign

0.016

MetaRNN

Benign

0.025

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.0

PhyloP100

0.35

PrimateAI

Benign

0.29

PROVEAN

Benign

0.31

REVEL

Benign

0.040

Sift

Benign

0.79

Sift4G

Benign

0.53

Polyphen

0.0

Vest4

0.18

MVP

0.27

MPC

0.047

ClinPred

0.030

GERP RS

2.0

Varity_R

0.044

gMVP

0.045

Mutation Taster

=85/15

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over