Genetic Variant HFM1:c.3884-4A>T (chr1-91266111-T-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_001017975.6(HFM1):c.3884-4A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000336 in 1,588,128 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0020 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 1 hom. )

Consequence

HFM1
NM_001017975.6 splice_region, intron

Scores

Splicing: ADA: 0.00009429

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.643

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: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP6

Variant 1-91266111-T-A is Benign according to our data. Variant chr1-91266111-T-A is described in ClinVar as Likely_benign. ClinVar VariationId is 595665.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 4 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.3884-4A>T		splice_region intron	N/A	NP_001017975.5	A2PYH4-1
	HFM1	NR_165455.1		n.3474-4A>T		splice_region intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HFM1	ENST00000370425.8	TSL:1 MANE Select	c.3884-4A>T	splice_region intron	N/A	ENSP00000359454.3	A2PYH4-1
HFM1	ENST00000430465.1	TSL:1	c.1517-4A>T	splice_region intron	N/A	ENSP00000387661.1	H0Y3X7
HFM1	ENST00000462405.5	TSL:2	n.1809+1634A>T	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00198

AC:

302

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00710

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.00

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.000502

AC:

112

AN:

223324

AF XY:

0.000386

show subpopulations

Gnomad AFR exome

AF:

0.00753

Gnomad AMR exome

AF:

0.000182

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000190

Gnomad OTH exome

AF:

0.000187

GnomAD4 exome

AF:

0.000159

AC:

229

AN:

1435826

Hom.:

Cov.:

AF XY:

0.000132

AC XY:

AN XY:

714244

show subpopulations

African (AFR)

AF:

0.00638

AC:

198

AN:

31036

American (AMR)

AF:

0.000294

AC:

AN:

37390

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25276

East Asian (EAS)

AF:

0.00

AC:

AN:

38178

South Asian (SAS)

AF:

0.00

AC:

AN:

81808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53186

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5650

European-Non Finnish (NFE)

AF:

0.00000181

AC:

AN:

1103954

Other (OTH)

AF:

0.000303

AC:

AN:

59348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00200

AC:

304

AN:

152302

Hom.:

Cov.:

AF XY:

0.00204

AC XY:

152

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.00712

AC:

296

AN:

41554

American (AMR)

AF:

0.000327

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68020

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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:

0.000630

Hom.:

Bravo

AF:

0.00229

ClinVar

ClinVar submissions

Significance:Likely benign

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

BayesDel_noAF

Benign

-0.63

CADD

Benign

1.2

(source)

DANN

Benign

0.82

PhyloP100

-0.64

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000094

dbscSNV1_RF

Benign

0.0020

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over