rs375403709

Variant names:

• chr1-91274787-C-A
• rs375403709
• NM_001017975.6:c.3611G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-91274787-C-A
• chr1-91274787-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001017975.6(HFM1):​c.3611G>T​(p.Ser1204Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000127 in 1,571,106 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1204N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: HFM1 NM_001017975.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.350
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.120717764).

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.3611G>T	p.Ser1204Ile	missense	Exon 33 of 39	NP_001017975.5	A2PYH4-1
	HFM1	NR_165455.1		n.3201G>T		non_coding_transcript_exon	Exon 27 of 33

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HFM1	ENST00000370425.8	TSL:1 MANE Select	c.3611G>T	p.Ser1204Ile	missense	Exon 33 of 39	ENSP00000359454.3	A2PYH4-1
	HFM1	ENST00000430465.1	TSL:1	c.1244G>T	p.Ser415Ile	missense	Exon 14 of 19	ENSP00000387661.1	H0Y3X7
	HFM1	ENST00000462405.5	TSL:2	n.1537G>T		non_coding_transcript_exon	Exon 16 of 21

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 247600 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 7.05e-7 AC: 1 AN: 1418970 Hom.: 0 Cov.: 23 AF XY: 0.00000141 AC XY: 1 AN XY: 708148

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32648

American (AMR) AF: 0.00 AC: 0 AN: 44054

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25800

East Asian (EAS) AF: 0.00 AC: 0 AN: 39348

South Asian (SAS) AF: 0.00 AC: 0 AN: 83594

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53296

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5582

European-Non Finnish (NFE) AF: 9.30e-7 AC: 1 AN: 1075684

Other (OTH) AF: 0.00 AC: 0 AN: 58964

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152136 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74332

African (AFR) AF: 0.00 AC: 0 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Benign	0.029	T
Eigen	Benign	-0.091
Eigen_PC	Benign	-0.092
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.35
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.037
Sift	Benign	0.075	T
Sift4G	Uncertain	0.044	D
Polyphen		0.16	B
Vest4		0.44
MutPred		0.26		Loss of disorder (P = 0.0142)
MVP		0.33
MPC		0.064
ClinPred		0.46	T
GERP RS		2.0
Varity_R		0.10
gMVP		0.18
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs375403709; hg19: chr1-91740344;