chr18-21383674-AG-A

Position:

• chr18-21383674-AG-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PM2 PP3_Moderate PP5_Moderate

The NM_001142966.3(GREB1L):​c.157+1del variant causes a frameshift, splice region change. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GREB1L NM_001142966.3 frameshift, splice_region
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.00

Genes affected

GREB1L (HGNC:31042): (GREB1 like retinoic acid receptor coactivator) Acts upstream of or within kidney development. Predicted to be integral component of membrane. Implicated in autosomal dominant nonsyndromic deafness and renal agenesis. [provided by Alliance of Genome Resources, Apr 2022]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 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
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 18-21383674-AG-A is Pathogenic according to our data. Variant chr18-21383674-AG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 982418.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GREB1L	NM_001142966.3	c.157+1del		frameshift_variant, splice_region_variant	3/33	ENST00000424526.7	NP_001136438.1
LOC101927521	XR_001753366.2	n.245-3000del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GREB1L	ENST00000424526.7	c.157+1del		frameshift_variant, splice_region_variant	3/33	5	NM_001142966.3	ENSP00000412060
	ENST00000584611.1	n.290-3000del		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Renal hypodysplasia/aplasia 3 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Jul 14, 2020

ACMG codes:PVS1, PM2 -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.75		Position offset: 0
DS_DL_spliceai		0.97		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs2040417979; hg19: chr18-18963635;