Variant chr1-91261300-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_001017975.6(HFM1):c.4298G>A(p.Gly1433Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000144 in 1,354,444 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

HFM1
NM_001017975.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.535

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 links:

HFM1 (HGNC:):

HFM1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.013391048).

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000145 (22/152068) while in subpopulation SAS AF= 0.00124 (6/4828). AF 95% confidence interval is 0.000541. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HFM1	NM_001017975.6 linkuse as main transcript	c.4298G>A	p.Gly1433Asp	missense_variant	39/39	ENST00000370425.8	NP_001017975.5	A2PYH4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HFM1	ENST00000370425.8 linkuse as main transcript	c.4298G>A	p.Gly1433Asp	missense_variant	39/39	1	NM_001017975.6	ENSP00000359454.3		A2PYH4-1
HFM1	ENST00000462405.5 linkuse as main transcript	n.2133G>A		non_coding_transcript_exon_variant	21/21	2

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000144

AC:

173

AN:

1202376

Hom.:

Cov.:

AF XY:

0.000155

AC XY:

AN XY:

595374

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000470

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000318

Gnomad4 SAS exome

AF:

0.000530

Gnomad4 FIN exome

AF:

0.0000434

Gnomad4 NFE exome

AF:

0.000143

Gnomad4 OTH exome

AF:

0.000101

GnomAD4 genome

AF:

0.000145

AC:

AN:

152068

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74274

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000199

Hom.:

Bravo

AF:

0.000102

ExAC

AF:

0.0000774

AC:

Asia WGS

AF:

0.000871

AC:

AN:

3460

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 05, 2024

The c.4298G>A (p.G1433D) alteration is located in exon 39 (coding exon 38) of the HFM1 gene. This alteration results from a G to A substitution at nucleotide position 4298, causing the glycine (G) at amino acid position 1433 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.39

CADD

Benign

7.9

DANN

Benign

0.95

DEOGEN2

Benign

0.0091

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.094

LIST_S2

Benign

0.57

M_CAP

Benign

0.040

MetaRNN

Benign

0.013

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.42

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.56

REVEL

Benign

0.19

Sift

Benign

0.34

Sift4G

Benign

0.064

Polyphen

0.0070

Vest4

0.22

MVP

0.26

MPC

0.063

ClinPred

0.043

GERP RS

2.5

Varity_R

0.046

gMVP

0.35

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over