chr1-91273778-C-T

Variant summary

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

The NM_001017975.6(HFM1):​c.3706G>A​(p.Glu1236Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,445,424 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

HFM1
NM_001017975.6 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.449
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 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=0.117608875).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HFM1NM_001017975.6 linkc.3706G>A p.Glu1236Lys missense_variant Exon 34 of 39 ENST00000370425.8 NP_001017975.5 A2PYH4-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HFM1ENST00000370425.8 linkc.3706G>A p.Glu1236Lys missense_variant Exon 34 of 39 1 NM_001017975.6 ENSP00000359454.3 A2PYH4-1
HFM1ENST00000430465.1 linkc.1339G>A p.Glu447Lys missense_variant Exon 15 of 19 1 ENSP00000387661.1 H0Y3X7
HFM1ENST00000462405.5 linkn.1632G>A non_coding_transcript_exon_variant Exon 17 of 21 2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.92e-7
AC:
1
AN:
1445424
Hom.:
0
Cov.:
27
AF XY:
0.00
AC XY:
0
AN XY:
720204
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000117
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 09, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.3706G>A (p.E1236K) alteration is located in exon 34 (coding exon 33) of the HFM1 gene. This alteration results from a G to A substitution at nucleotide position 3706, causing the glutamic acid (E) at amino acid position 1236 to be replaced by a lysine (K). 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
0.069
BayesDel_addAF
Benign
-0.075
T
BayesDel_noAF
Benign
-0.35
CADD
Benign
11
DANN
Uncertain
0.98
DEOGEN2
Benign
0.013
T
Eigen
Benign
-0.33
Eigen_PC
Benign
-0.36
FATHMM_MKL
Benign
0.088
N
LIST_S2
Benign
0.66
T
M_CAP
Benign
0.039
D
MetaRNN
Benign
0.12
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.2
M
PrimateAI
Benign
0.40
T
PROVEAN
Benign
-0.58
N
REVEL
Benign
0.077
Sift
Benign
0.15
T
Sift4G
Benign
0.34
T
Polyphen
0.0030
B
Vest4
0.26
MutPred
0.37
Gain of ubiquitination at E1236 (P = 0.017);
MVP
0.28
MPC
0.054
ClinPred
0.42
T
GERP RS
2.3
Varity_R
0.044
gMVP
0.13

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.

Other links and lift over

dbSNP: rs1666541200; hg19: chr1-91739335; API