chr1-91267768-T-A

Variant summary

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

The NM_001017975.6(HFM1):​c.3860A>T​(p.Asp1287Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000625 in 1,520,392 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.000053 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000064 ( 1 hom. )

Consequence

HFM1
NM_001017975.6 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.04
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]

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=0.056628793).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
HFM1NM_001017975.6 linkuse as main transcriptc.3860A>T p.Asp1287Val missense_variant 35/39 ENST00000370425.8 NP_001017975.5 A2PYH4-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
HFM1ENST00000370425.8 linkuse as main transcriptc.3860A>T p.Asp1287Val missense_variant 35/391 NM_001017975.6 ENSP00000359454.3 A2PYH4-1
HFM1ENST00000430465.1 linkuse as main transcriptc.1493A>T p.Asp498Val missense_variant 16/191 ENSP00000387661.1 H0Y3X7
HFM1ENST00000462405.5 linkuse as main transcriptn.1786A>T non_coding_transcript_exon_variant 18/212

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152174
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.0000147
Gnomad OTH
AF:
0.000479
GnomAD3 exomes
AF:
0.0000559
AC:
12
AN:
214600
Hom.:
1
AF XY:
0.0000512
AC XY:
6
AN XY:
117284
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000214
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000859
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000385
Gnomad OTH exome
AF:
0.000196
GnomAD4 exome
AF:
0.0000636
AC:
87
AN:
1368100
Hom.:
1
Cov.:
23
AF XY:
0.0000731
AC XY:
50
AN XY:
684120
show subpopulations
Gnomad4 AFR exome
AF:
0.000204
Gnomad4 AMR exome
AF:
0.000268
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000388
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000542
Gnomad4 OTH exome
AF:
0.000158
GnomAD4 genome
AF:
0.0000525
AC:
8
AN:
152292
Hom.:
0
Cov.:
33
AF XY:
0.0000671
AC XY:
5
AN XY:
74464
show subpopulations
Gnomad4 AFR
AF:
0.000120
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.000474
Alfa
AF:
0.0000565
Hom.:
0
Bravo
AF:
0.0000529
ExAC
AF:
0.0000330
AC:
4

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 submitterclinical testingAmbry GeneticsMay 07, 2024The c.3860A>T (p.D1287V) alteration is located in exon 35 (coding exon 34) of the HFM1 gene. This alteration results from a A to T substitution at nucleotide position 3860, causing the aspartic acid (D) at amino acid position 1287 to be replaced by a valine (V). 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
0.088
BayesDel_addAF
Benign
-0.25
T
BayesDel_noAF
Benign
-0.32
CADD
Benign
19
DANN
Benign
0.97
DEOGEN2
Benign
0.023
T
Eigen
Benign
-0.29
Eigen_PC
Benign
-0.35
FATHMM_MKL
Benign
0.11
N
LIST_S2
Benign
0.68
T
M_CAP
Benign
0.011
T
MetaRNN
Benign
0.057
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.1
M
PrimateAI
Benign
0.25
T
PROVEAN
Benign
-1.6
N
REVEL
Benign
0.17
Sift
Uncertain
0.0030
D
Sift4G
Benign
0.38
T
Polyphen
0.66
P
Vest4
0.21
MVP
0.18
MPC
0.11
ClinPred
0.13
T
GERP RS
4.0
Varity_R
0.12
gMVP
0.12

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.11
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.

Other links and lift over

dbSNP: rs200074366; hg19: chr1-91733325; API