rs143399622

Positions:

• chr1-91343457-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The ENST00000370425.8(HFM1):​c.2308G>A​(p.Asp770Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00272 in 1,444,094 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (9 hom.)
• Consequence: HFM1 ENST00000370425.8 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.64

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 1-91343457-C-T is Benign according to our data. Variant chr1-91343457-C-T is described in ClinVar as [Benign]. Clinvar id is 435416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00222 (337/152020) while in subpopulation NFE AF= 0.0041 (279/67990). AF 95% confidence interval is 0.00371. There are 1 homozygotes in gnomad4. There are 142 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HFM1	NM_001017975.6	c.2308G>A	p.Asp770Asn	missense_variant	20/39	ENST00000370425.8	NP_001017975.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HFM1	ENST00000370425.8	c.2308G>A	p.Asp770Asn	missense_variant	20/39	1	NM_001017975.6	ENSP00000359454	P1
HFM1	ENST00000430465.1	c.76G>A	p.Asp26Asn	missense_variant	2/19	1		ENSP00000387661
HFM1	ENST00000462405.5	n.234G>A		non_coding_transcript_exon_variant	3/21	2

Frequencies

GnomAD3 genomes AF: 0.00222 AC: 337 AN: 152020 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000942

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000394

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000756

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00410

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00184 AC: 370 AN: 201368 Hom.: 2 AF XY: 0.00195 AC XY: 213 AN XY: 109066

Gnomad AFR exome AF: 0.000568

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.000670

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000633

Gnomad NFE exome AF: 0.00361

Gnomad OTH exome AF: 0.00105

GnomAD4 exome AF: 0.00278 AC: 3595 AN: 1292074 Hom.: 9 Cov.: 19 AF XY: 0.00270 AC XY: 1744 AN XY: 646302

Gnomad4 AFR exome AF: 0.000384

Gnomad4 AMR exome AF: 0.000348

Gnomad4 ASJ exome AF: 0.00103

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000694

Gnomad4 NFE exome AF: 0.00349

Gnomad4 OTH exome AF: 0.00142

GnomAD4 genome AF: 0.00222 AC: 337 AN: 152020 Hom.: 1 Cov.: 32 AF XY: 0.00191 AC XY: 142 AN XY: 74266

Gnomad4 AFR AF: 0.000942

Gnomad4 AMR AF: 0.000394

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000756

Gnomad4 NFE AF: 0.00410

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.00325 Hom.: 3

Bravo AF: 0.00203

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.000685 AC: 3

ESP6500EA AF: 0.00353 AC: 30

ExAC AF: 0.00178 AC: 216

Asia WGS AF: 0.000289 AC: 1 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 24, 2017

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

HFM1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 03, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.28
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.51
MVP		0.26
MPC		0.18
ClinPred		0.043	T
GERP RS		5.3
Varity_R		0.36
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.26		Position offset: -27

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

Publications

LitVar

Other links and lift over

dbSNP: rs143399622; hg19: chr1-91809014;