dbSNP rs777263062: PMFBP1:p.Gln488* (chr16-72130708-G-A) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_031293.3(PMFBP1):c.1462C>T(p.Gln488*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,459,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

PMFBP1
NM_031293.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 0.482

Publications

3 publications found

Variant links:

Genes affected

PMFBP1 (HGNC:17728): (polyamine modulated factor 1 binding protein 1) Involved in spermatogenesis. Located in sperm connecting piece. Implicated in spermatogenic failure 31. [provided by Alliance of Genome Resources, Apr 2022]

PMFBP1 Gene-Disease associations (from GenCC):

spermatogenic failure 31
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

PMFBP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-72130708-G-A is Pathogenic according to our data. Variant chr16-72130708-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 560417.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMFBP1	NM_031293.3 link	c.1462C>T	p.Gln488*	stop_gained	Exon 11 of 21	ENST00000237353.15	NP_112583.2	Q8TBY8-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMFBP1	ENST00000237353.15 link	c.1462C>T	p.Gln488*	stop_gained	Exon 11 of 21	1	NM_031293.3	ENSP00000237353.10		Q8TBY8-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000403

AC:

AN:

248054

AF XY:

0.00000746

show subpopulations

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:

0.00000343

AC:

AN:

1459720

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

726142

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33454

American (AMR)

AF:

0.00

AC:

AN:

44656

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26088

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.0000581

AC:

AN:

86118

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52020

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5710

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111638

Other (OTH)

AF:

0.00

AC:

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.435

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Spermatogenic failure 31

Pathogenic:2

Sep 07, 2018

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Apr 21, 2023

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A heterozygous missense variation in exon 11 of the PMFBP1 gene that results in premature stop codon was detected.. The observed variant c.1462C>T(p.Gln488Ter) not observed in the 1000Genomes database and have MAF of 0.0003% in the gnomAD database. The in silico prediction of the variant is damaging by BayesDEL. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a variant of uncertain significance. The observed variant was validated in mother and father using sanger sequencing. The variant was detected in heterozygous state in father, whereas was wildtype in mother. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Uncertain

0.23

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.064

PhyloP100

0.48

Vest4

0.11

GERP RS

1.6

Mutation Taster

=5/195

disease causing (ClinVar)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over