1-91262277-A-T

Position:

• chr1-91262277-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001017975.6(HFM1):​c.4202T>A​(p.Ile1401Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HFM1 NM_001017975.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.59

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HFM1	NM_001017975.6	c.4202T>A	p.Ile1401Asn	missense_variant	38/39	ENST00000370425.8	NP_001017975.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HFM1	ENST00000370425.8	c.4202T>A	p.Ile1401Asn	missense_variant	38/39	1	NM_001017975.6	ENSP00000359454.3
HFM1	ENST00000430465.1	c.1835T>A	p.Ile612Asn	missense_variant	19/19	1		ENSP00000387661.1
HFM1	ENST00000462405.5	n.2037T>A		non_coding_transcript_exon_variant	20/21	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 22

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 12, 2023

The c.4202T>A (p.I1401N) alteration is located in exon 38 (coding exon 37) of the HFM1 gene. This alteration results from a T to A substitution at nucleotide position 4202, causing the isoleucine (I) at amino acid position 1401 to be replaced by an asparagine (N). 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	0.11
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.025	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	L
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.15
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.55	P
Vest4		0.59
MutPred		0.53		Loss of sheet (P = 0.0054);
MVP		0.28
MPC		0.19
ClinPred		0.63	D
GERP RS		3.7
Varity_R		0.35
gMVP		0.41

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

Publications

LitVar

Other links and lift over

dbSNP: rs1665234607; hg19: chr1-91727834;