dbSNP rs143399622: HFM1:p.Asp770Asn (chr1-91343457-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_StrongBS2

The NM_001017975.6(HFM1):c.2308G>A(p.Asp770Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00272 in 1,444,094 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0022 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0028 ( 9 hom. )

Consequence

HFM1
NM_001017975.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 5.64

Publications

7 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: Benign. The variant received -12 ACMG points.

BP6

Variant 1-91343457-C-T is Benign according to our data. Variant chr1-91343457-C-T is described in ClinVar as Benign. ClinVar VariationId is 435416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 9 AR,Unknown gene

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.2308G>A	p.Asp770Asn	missense	Exon 20 of 39	NP_001017975.5	A2PYH4-1
	HFM1	NR_165455.1		n.2118+3972G>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HFM1	ENST00000370425.8	TSL:1 MANE Select	c.2308G>A	p.Asp770Asn	missense	Exon 20 of 39	ENSP00000359454.3	A2PYH4-1
HFM1	ENST00000430465.1	TSL:1	c.73G>A	p.Asp25Asn	missense	Exon 2 of 19	ENSP00000387661.1	H0Y3X7
HFM1	ENST00000462405.5	TSL:2	n.234G>A		non_coding_transcript_exon	Exon 3 of 21

Frequencies

GnomAD3 genomes

AF:

0.00222

AC:

337

AN:

152020

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000942

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000394

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000756

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00410

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00184

AC:

370

AN:

201368

AF XY:

0.00195

show subpopulations

Gnomad AFR exome

AF:

0.000568

Gnomad AMR exome

AF:

0.000348

Gnomad ASJ exome

AF:

0.000670

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000633

Gnomad NFE exome

AF:

0.00361

Gnomad OTH exome

AF:

0.00105

GnomAD4 exome

AF:

0.00278

AC:

3595

AN:

1292074

Hom.:

Cov.:

AF XY:

0.00270

AC XY:

1744

AN XY:

646302

show subpopulations

African (AFR)

AF:

0.000384

AC:

AN:

28676

American (AMR)

AF:

0.000348

AC:

AN:

37338

Ashkenazi Jewish (ASJ)

AF:

0.00103

AC:

AN:

24276

East Asian (EAS)

AF:

0.00

AC:

AN:

36354

South Asian (SAS)

AF:

0.00

AC:

AN:

70358

European-Finnish (FIN)

AF:

0.000694

AC:

AN:

51860

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5446

European-Non Finnish (NFE)

AF:

0.00349

AC:

3433

AN:

983648

Other (OTH)

AF:

0.00142

AC:

AN:

54118

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.441

Heterozygous variant carriers

124

247

371

494

618

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

122

244

366

488

610

<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:

0.00222

AC:

337

AN:

152020

Hom.:

Cov.:

AF XY:

0.00191

AC XY:

142

AN XY:

74266

show subpopulations

African (AFR)

AF:

0.000942

AC:

AN:

41394

American (AMR)

AF:

0.000394

AC:

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000756

AC:

AN:

10578

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00410

AC:

279

AN:

67990

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00301

Hom.:

Bravo

AF:

0.00203

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.000685

AC:

ESP6500EA

AF:

0.00353

AC:

ExAC

AF:

0.00178

AC:

216

Asia WGS

AF:

0.000289

AC:

AN:

3472

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

HFM1-related disorder (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.43

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.029

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.57

MutationAssessor

Uncertain

2.0

PhyloP100

5.6

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.6

REVEL

Benign

0.28

Sift

Uncertain

0.024

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.51

MVP

0.26

MPC

0.18

ClinPred

0.043

GERP RS

5.3

Varity_R

0.36

gMVP

0.58

Mutation Taster

=66/34

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.26

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.26

Position offset: -27

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over