chr18-21395412-G-A

Position:

• chr18-21395412-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_001142966.3(GREB1L):​c.383G>A​(p.Arg128His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as association (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: GREB1L NM_001142966.3 missense
• Clinical Significance: association no assertion criteria provided O:1
• Conservation: PhyloP100: 10.0

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GREB1L. . Gene score misZ 5.3659 (greater than the threshold 3.09). Trascript score misZ 5.6738 (greater than threshold 3.09). GenCC has associacion of gene with bilateral renal agenesis, renal hypodysplasia/aplasia 3, renal agenesis, unilateral, hearing loss, autosomal dominant 80.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.802

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GREB1L	NM_001142966.3	c.383G>A	p.Arg128His	missense_variant	5/33	ENST00000424526.7	NP_001136438.1
LOC101927521	XR_001753366.2	n.244+6409C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GREB1L	ENST00000424526.7	c.383G>A	p.Arg128His	missense_variant	5/33	5	NM_001142966.3	ENSP00000412060
	ENST00000584611.1	n.214+6409C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: association

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Renal agenesis and hypodysplasia Other:1

association, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

Nov 02, 2017

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.034	T;.;T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;.
M_CAP	Benign	0.028	D
MetaRNN	Pathogenic	0.80	D;D;D
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.9	L;L;L
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.8	D;D;.
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.92
MutPred		0.62		Gain of methylation at K125 (P = 0.046);Gain of methylation at K125 (P = 0.046);Gain of methylation at K125 (P = 0.046);
MVP		0.35
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.57
gMVP		0.49

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: rs1598751507; hg19: chr18-18975373; COSMIC: COSV52551926;