1-91261300-C-T

Variant names:

• chr1-91261300-C-T
• rs759959365
• NM_001017975.6:c.4298G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

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. 16/22 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.535
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• premature ovarian failure 9

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• male infertility with azoospermia or oligozoospermia due to single gene mutation

  Inheritance: AR Classification: NO_KNOWN Submitted by: King Faisal Specialist Hospital and Research Center

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013391048).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001017975.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HFM1	NM_001017975.6	MANE Select	c.4298G>A	p.Gly1433Asp	missense	Exon 39 of 39	NP_001017975.5	A2PYH4-1
	HFM1	NR_165455.1		n.3888G>A		non_coding_transcript_exon	Exon 33 of 33

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HFM1	ENST00000370425.8	TSL:1 MANE Select	c.4298G>A	p.Gly1433Asp	missense	Exon 39 of 39	ENSP00000359454.3	A2PYH4-1
	HFM1	ENST00000462405.5	TSL:2	n.2133G>A		non_coding_transcript_exon	Exon 21 of 21

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152068 Hom.: 0 Cov.: 33

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

GnomAD2 exomes AF: 0.000120 AC: 14 AN: 116666 AF XY: 0.000140

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000861

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000151

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000144 AC: 173 AN: 1202376 Hom.: 0 Cov.: 17 AF XY: 0.000155 AC XY: 92 AN XY: 595374

African (AFR) AF: 0.00 AC: 0 AN: 24798

American (AMR) AF: 0.0000470 AC: 1 AN: 21268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20802

East Asian (EAS) AF: 0.0000318 AC: 1 AN: 31438

South Asian (SAS) AF: 0.000530 AC: 28 AN: 52852

European-Finnish (FIN) AF: 0.0000434 AC: 2 AN: 46104

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5038

European-Non Finnish (NFE) AF: 0.000143 AC: 136 AN: 950734

Other (OTH) AF: 0.000101 AC: 5 AN: 49342

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152068 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74274

African (AFR) AF: 0.000121 AC: 5 AN: 41414

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5208

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 67964

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000199 Hom.: 0

Bravo AF: 0.000102

ExAC AF: 0.0000774 AC: 9

Asia WGS AF: 0.000871 AC: 3 AN: 3460

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	7.9
DANN	Benign	0.95
DEOGEN2	Benign	0.0091	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.094	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.42	N
PhyloP100		-0.54
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.19
Sift	Benign	0.34	T
Sift4G	Benign	0.064	T
Polyphen		0.0070	B
Vest4		0.22
MVP		0.26
MPC		0.063
ClinPred		0.043	T
GERP RS		2.5
Varity_R		0.046
gMVP		0.35
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs759959365; hg19: chr1-91726857; COSMIC: COSV99645883;