Variant 1-91274758-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001017975.6(HFM1):c.3640C>G(p.Pro1214Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00012 in 1,561,634 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 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

HFM1
NM_001017975.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.28

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11231163).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HFM1	NM_001017975.6 linkuse as main transcript	c.3640C>G	p.Pro1214Ala	missense_variant	33/39	ENST00000370425.8	NP_001017975.5	A2PYH4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HFM1	ENST00000370425.8 linkuse as main transcript	c.3640C>G	p.Pro1214Ala	missense_variant	33/39	1	NM_001017975.6	ENSP00000359454.3	A2PYH4-1
HFM1	ENST00000430465.1 linkuse as main transcript	c.1273C>G	p.Pro425Ala	missense_variant	14/19	1		ENSP00000387661.1	H0Y3X7
HFM1	ENST00000462405.5 linkuse as main transcript	n.1566C>G		non_coding_transcript_exon_variant	16/21	2

Frequencies

GnomAD3 genomes

AF:

0.0000921

AC:

AN:

152040

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000109

AC:

AN:

248010

Hom.:

AF XY:

0.000142

AC XY:

AN XY:

134200

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000301

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000221

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.000123

AC:

174

AN:

1409594

Hom.:

Cov.:

AF XY:

0.000131

AC XY:

AN XY:

703948

show subpopulations

Gnomad4 AFR exome

AF:

0.0000308

Gnomad4 AMR exome

AF:

0.0000227

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.000157

Gnomad4 OTH exome

AF:

0.0000512

GnomAD4 genome

AF:

0.0000921

AC:

AN:

152040

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74272

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000179

Hom.:

Bravo

AF:

0.000102

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.0000989

AC:

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

Nov 06, 2023

The c.3640C>G (p.P1214A) alteration is located in exon 33 (coding exon 32) of the HFM1 gene. This alteration results from a C to G substitution at nucleotide position 3640, causing the proline (P) at amino acid position 1214 to be replaced by an alanine (A). 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

0.078

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.070

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.64

M_CAP

Benign

0.025

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.058

Sift

Benign

0.049

Sift4G

Benign

0.15

Polyphen

0.015

Vest4

0.28

MVP

0.27

MPC

0.052

ClinPred

0.066

GERP RS

3.4

Varity_R

0.11

gMVP

0.18

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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