rs1555661490

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 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
• 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: Ambry Genetics, Illumina, G2P, Labcorp Genetics (formerly Invitae)
• 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)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious 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 VariationId is 446527.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.4368G>T	p.Gln1456His	missense splice_region	Exon 25 of 33	NP_001136438.1	Q9C091-1
	GREB1L	NM_001410867.1		c.4497G>T	p.Gln1499His	missense splice_region	Exon 26 of 34	NP_001397796.1	J3QQW0
	GREB1L	NM_001410868.1		c.4041G>T	p.Gln1347His	missense splice_region	Exon 24 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.4368G>T	p.Gln1456His	missense splice_region	Exon 25 of 33	ENSP00000412060.1	Q9C091-1
	GREB1L	ENST00000861016.1		c.4497G>T	p.Gln1499His	missense splice_region	Exon 27 of 35	ENSP00000531075.1
	GREB1L	ENST00000579454.2	TSL:5	c.4497G>T	p.Gln1499His	missense splice_region	Exon 26 of 34	ENSP00000463926.2	J3QQW0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Hearing loss, autosomal dominant 80 (1)
1	-	-	Inner ear malformation (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.075	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Uncertain	-0.083	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		9.6
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.87	P
Vest4		0.59
MutPred		0.20		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
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1555661490; hg19: chr18-19085910;