rs1555661490

Variant names:

• chr18-21505949-G-T
• rs1555661490
• NM_001142966.3:c.4368G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_001142966.3(GREB1L):​c.4368G>T​(p.Gln1456His) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GREB1L NM_001142966.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 9.60

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the GREB1L gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 17 curated pathogenic missense variants (we use a threshold of 10). The gene has 23 curated benign missense variants. Gene score misZ: 5.3659 (above the threshold of 3.09). Trascript score misZ: 5.6738 (above the threshold of 3.09). GenCC associations: The gene is linked to bilateral renal agenesis, renal hypodysplasia/aplasia 3, renal agenesis, unilateral, hearing loss, autosomal dominant 80.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 18-21505949-G-T is Pathogenic according to our data. Variant chr18-21505949-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 446527.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr18-21505949-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GREB1L	NM_001142966.3	c.4368G>T	p.Gln1456His	missense_variant, splice_region_variant	Exon 25 of 33	ENST00000424526.7	NP_001136438.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GREB1L	ENST00000424526.7	c.4368G>T	p.Gln1456His	missense_variant, splice_region_variant	Exon 25 of 33	5	NM_001142966.3	ENSP00000412060.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Inner ear malformation Pathogenic:1

Nov 25, 2017

Center for Statistical Genetics, Columbia University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

de novo mutation -

Hearing loss, autosomal dominant 80 Pathogenic:1

Apr 14, 2021

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	36
DANN	Uncertain	1.0
DEOGEN2	Benign	0.045	T;.;T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.75	T;T;.
M_CAP	Benign	0.075	D
MetaRNN	Uncertain	0.62	D;D;D
MetaSVM	Uncertain	-0.083	T
MutationAssessor	Uncertain	2.3	M;.;M
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.8	D;D;.
REVEL	Uncertain	0.39
Sift	Uncertain	0.0010	D;D;.
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		0.87	P;D;P
Vest4		0.59
MutPred		0.20		Gain of glycosylation at S1460 (P = 0.1276);.;Gain of glycosylation at S1460 (P = 0.1276);
MVP		0.47
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.71
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.91		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.66		Position offset: 37
DS_DL_spliceai		0.91		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555661490; hg19: chr18-19085910;