rs777707946

Variant names:

• chr18-21383555-C-T
• rs777707946
• NM_001142966.3:c.37C>T

Your query was ambiguous. Multiple possible variants found:

• chr18-21383555-C-T
• chr18-21383555-C-G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001142966.3(GREB1L):​c.37C>T​(p.Arg13*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000215 in 1,394,100 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 Likely pathogenic,association (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: GREB1L NM_001142966.3 stop_gained
• Clinical Significance: Likely pathogenic; association no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 5.87
• Publications: 0 publications found

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]

GREB1L Gene-Disease associations (from GenCC):

• renal hypodysplasia/aplasia 3

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Illumina, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• renal agenesis, unilateral

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• bilateral renal agenesis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal dominant 80

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

GREB1L-AS1 (HGNC:58310):

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 74 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-21383555-C-T is Pathogenic according to our data. Variant chr18-21383555-C-T is described in ClinVar as Likely_pathogenic|association. ClinVar VariationId is 684652.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142966.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GREB1L	NM_001142966.3	MANE Select	c.37C>T	p.Arg13*	stop_gained	Exon 3 of 33	NP_001136438.1	Q9C091-1
	GREB1L	NM_001410867.1		c.37C>T	p.Arg13*	stop_gained	Exon 3 of 34	NP_001397796.1	J3QQW0
	GREB1L	NM_001410868.1		c.37C>T	p.Arg13*	stop_gained	Exon 3 of 32	NP_001397797.1	Q9C091-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GREB1L	ENST00000424526.7	TSL:5 MANE Select	c.37C>T	p.Arg13*	stop_gained	Exon 3 of 33	ENSP00000412060.1	Q9C091-1
	GREB1L	ENST00000578368.5	TSL:1	n.142C>T		non_coding_transcript_exon	Exon 2 of 15
	GREB1L	ENST00000584446.5	TSL:1	n.308C>T		non_coding_transcript_exon	Exon 3 of 15

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000215 AC: 3 AN: 1394100 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 687396

African (AFR) AF: 0.00 AC: 0 AN: 31262

American (AMR) AF: 0.00 AC: 0 AN: 34454

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25094

East Asian (EAS) AF: 0.00 AC: 0 AN: 35496

South Asian (SAS) AF: 0.00 AC: 0 AN: 77678

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49268

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 0.00000278 AC: 3 AN: 1077328

Other (OTH) AF: 0.00 AC: 0 AN: 57834

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000329 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic; association

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Renal hypodysplasia/aplasia 3 (1)
-	-	-	Renal agenesis and hypodysplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		5.9
Vest4		0.42
GERP RS		4.5
Mutation Taster		=0/200	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs777707946; hg19: chr18-18963516;