chr16-1984414-TC-T

Position:

chr16-1984414-TC-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_005262.3(GFER):c.199del(p.Arg67GlyfsTer83) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000243 in 1,541,718 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00026 ( 0 hom. )

Consequence

GFER
NM_005262.3 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 1.28

Variant links:

Genes affected

GFER (HGNC:4236): (growth factor, augmenter of liver regeneration) The hepatotrophic factor designated augmenter of liver regeneration (ALR) is thought to be one of the factors responsible for the extraordinary regenerative capacity of mammalian liver. It has also been called hepatic regenerative stimulation substance (HSS). The gene resides on chromosome 16 in the interval containing the locus for polycystic kidney disease (PKD1). The putative gene product is 42% similar to the scERV1 protein of yeast. The yeast scERV1 gene had been found to be essential for oxidative phosphorylation, the maintenance of mitochondrial genomes, and the cell division cycle. The human gene is both the structural and functional homolog of the yeast scERV1 gene. [provided by RefSeq, Jul 2008]

GFER links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 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 16-1984414-TC-T is Pathogenic according to our data. Variant chr16-1984414-TC-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 214476.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GFER	NM_005262.3 linkuse as main transcript	c.199del	p.Arg67GlyfsTer83	frameshift_variant	1/3	ENST00000248114.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFER	ENST00000248114.7 linkuse as main transcript	c.199del	p.Arg67GlyfsTer83	frameshift_variant	1/3	1	NM_005262.3	P1	P55789-1
GFER	ENST00000565658.1 linkuse as main transcript	n.86del		non_coding_transcript_exon_variant	1/2	1
GFER	ENST00000561710.1 linkuse as main transcript	c.160del	p.Arg54GlyfsTer83	frameshift_variant	1/2	2
GFER	ENST00000569451.1 linkuse as main transcript	c.199del	p.Arg67GlyfsTer74	frameshift_variant	1/2	5

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000443

AC:

AN:

135570

Hom.:

AF XY:

0.0000672

AC XY:

AN XY:

74442

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000118

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000264

AC:

367

AN:

1389554

Hom.:

Cov.:

AF XY:

0.000271

AC XY:

186

AN XY:

685898

show subpopulations

Gnomad4 AFR exome

AF:

0.0000632

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000335

Gnomad4 OTH exome

AF:

0.0000519

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000174

Hom.:

Bravo

AF:

0.0000453

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 14, 2018	c.199delC:p.Arg67GlyfsX83 (R67GfsX83) in exon 1 of the GFER gene (NM_005262.2). The normal sequence with the base that is deleted in braces is: CTCC{C}GGAG. The c.199delC variant in the GFER gene causes a frameshift starting with codon Arginine 67, changes this amino acid to a Glycine residue and creates a premature Stop codon at position 83 of the new reading frame, denoted p.Arg67GlyfsX83. It has not been published as pathogenic, nor has it been reported as a benign polymorphism to our knowledge. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay; however, to date no frameshift variants have been reported in the GFER gene. The c.199delC variant is a good candidate for a pathogenic variant, but the possibility it may be a rare benign variant cannot be excluded. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 11, 2024	This sequence change creates a premature translational stop signal (p.Arg67Glyfs*83) in the GFER gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 139 amino acid(s) of the GFER protein. This variant is present in population databases (rs747241374, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with clinical features of GFER-related condition (PMID: 34732400). ClinVar contains an entry for this variant (Variation ID: 214476). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Mitochondrial disease

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Wellcome Centre for Mitochondrial Research, Newcastle University

Apr 07, 2017

- -

Congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Jul 26, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over