chr1-91350738-C-T

Variant names:

• chr1-91350738-C-T
• rs587777269
• NM_001017975.6:c.2206G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001017975.6(HFM1):​c.2206G>A​(p.Gly736Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000137 in 1,456,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HFM1 NM_001017975.6 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.11
• Publications: 4 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_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 1-91350738-C-T is Pathogenic according to our data. Variant chr1-91350738-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 126430.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HFM1	NM_001017975.6	c.2206G>A	p.Gly736Ser	missense_variant, splice_region_variant	Exon 18 of 39	ENST00000370425.8	NP_001017975.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HFM1	ENST00000370425.8	c.2206G>A	p.Gly736Ser	missense_variant, splice_region_variant	Exon 18 of 39	1	NM_001017975.6	ENSP00000359454.3
HFM1	ENST00000462405.5	n.132+1768G>A		intron_variant	Intron 1 of 20	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456906 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 724754

⚠️ 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: 33330

American (AMR) AF: 0.00 AC: 0 AN: 44444

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25986

East Asian (EAS) AF: 0.00 AC: 0 AN: 39418

South Asian (SAS) AF: 0.00 AC: 0 AN: 85724

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1109760

Other (OTH) AF: 0.00 AC: 0 AN: 60148

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Premature ovarian failure 9 Pathogenic:1

Mar 06, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.041	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-0.37	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		6.1
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.019	D
Sift4G	Benign	0.10	T
Polyphen		1.0	D
Vest4		0.91
MutPred		0.29		Gain of disorder (P = 0.0665);
MVP		0.51
MPC		0.32
ClinPred		0.98	D
GERP RS		5.4
Varity_R		0.27
gMVP		0.70
Mutation Taster		=19/81	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.94		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.94		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587777269; hg19: chr1-91816295;