16-1984432-CG-C

Position:

• chr16-1984432-CG-C

Variant summary

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

The ENST00000248114.7(GFER):​c.217del​(p.Ala73ProfsTer77) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. R72R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GFER ENST00000248114.7 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 4.76

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]

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 16-1984432-CG-C is Pathogenic according to our data. Variant chr16-1984432-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 559178.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-1984432-CG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFER	NM_005262.3	c.217del	p.Ala73ProfsTer77	frameshift_variant	1/3	ENST00000248114.7	NP_005253.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFER	ENST00000248114.7	c.217del	p.Ala73ProfsTer77	frameshift_variant	1/3	1	NM_005262.3	ENSP00000248114	P1
GFER	ENST00000565658.1	n.104del		non_coding_transcript_exon_variant	1/2	1
GFER	ENST00000561710.1	c.178del	p.Ala60ProfsTer77	frameshift_variant	1/2	2		ENSP00000456189
GFER	ENST00000569451.1	c.217del	p.Ala73ProfsTer68	frameshift_variant	1/2	5		ENSP00000456432

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	This frameshift mutation is categorized as deleterious according to ACMG guidelines (PMID:18414213) and was found once in our laboratory in trans with a pathogenic variant in a 13-year-old male with profound delays, tremulousness, respiratory distress, congenital ataracts, hypoglycemia, lactic acidemia, autistic features, scoliosis, pica, hypotonia, intermittent alopecia, osteoporosis, episodes of hypophosphatemia. Similarly affected sister had same compound heterozygous genotype. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 20, 2020	- -

not provided Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Mar 08, 2016

- -

Computational scores

Source: dbNSFP v4.3

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: rs1555486560; hg19: chr16-2034433;