Variant 1-91276702-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001017975.6(HFM1):c.3514A>G(p.Thr1172Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000321 in 1,559,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

HFM1
NM_001017975.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.573

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 -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.020751983).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HFM1	NM_001017975.6 linkuse as main transcript	c.3514A>G	p.Thr1172Ala	missense_variant	32/39	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.3514A>G	p.Thr1172Ala	missense_variant	32/39	1	NM_001017975.6	ENSP00000359454.3	A2PYH4-1
HFM1	ENST00000430465.1 linkuse as main transcript	c.1147A>G	p.Thr383Ala	missense_variant	13/19	1		ENSP00000387661.1	H0Y3X7
HFM1	ENST00000462405.5 linkuse as main transcript	n.1440A>G		non_coding_transcript_exon_variant	15/21	2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

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

GnomAD3 exomes

AF:

0.0000281

AC:

AN:

213720

Hom.:

AF XY:

0.0000171

AC XY:

AN XY:

116690

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000402

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000284

AC:

AN:

1407510

Hom.:

Cov.:

AF XY:

0.00000286

AC XY:

AN XY:

700242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000107

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000412

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

Jun 17, 2024

The c.3514A>G (p.T1172A) alteration is located in exon 32 (coding exon 31) of the HFM1 gene. This alteration results from a A to G substitution at nucleotide position 3514, causing the threonine (T) at amino acid position 1172 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

0.059

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.64

DEOGEN2

Benign

0.022

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.43

M_CAP

Benign

0.0070

MetaRNN

Benign

0.021

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.60

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.0

REVEL

Benign

0.11

Sift

Benign

0.35

Sift4G

Benign

0.76

Polyphen

0.0

Vest4

0.019

MutPred

0.11

Gain of helix (P = 0.0325);

MVP

0.067

MPC

0.049

ClinPred

0.035

GERP RS

-3.9

Varity_R

0.045

gMVP

0.10

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