rs777263062

Positions:

• chr16-72130708-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_031293.3(PMFBP1):​c.1462C>T​(p.Gln488Ter) 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
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.482

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 id is 560417.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMFBP1	NM_031293.3	c.1462C>T	p.Gln488Ter	stop_gained	11/21	ENST00000237353.15	NP_112583.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMFBP1	ENST00000237353.15	c.1462C>T	p.Gln488Ter	stop_gained	11/21	1	NM_031293.3	ENSP00000237353

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000403 AC: 1 AN: 248054 Hom.: 0 AF XY: 0.00000746 AC XY: 1 AN XY: 134064

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 SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1459720 Hom.: 0 Cov.: 32 AF XY: 0.00000551 AC XY: 4 AN XY: 726142

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000581

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Spermatogenic failure 31 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Apr 21, 2023	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 07, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Uncertain	0.23
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.064	N
MutationTaster	Benign	1.0	A;A;A
Vest4		0.11
GERP RS		1.6

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

LitVar

Other links and lift over

dbSNP: rs777263062; hg19: chr16-72164607;