18-21383512-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001142966.3(GREB1L):c.-7G>A variant causes a splice region, 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00136 in 1,530,720 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0075 (18 hom., cov: 31)
  • Exomes 𝑓: 0.00069 (11 hom.)
• Consequence: GREB1L NM_001142966.3 splice_region, 5_prime_UTR
• Scores: Splicing: ADA: 0.0001109
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.365

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 18-21383512-G-A is Benign according to our data. Variant chr18-21383512-G-A is described in ClinVar as [Benign]. Clinvar id is 3042873.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00747 (1137/152132) while in subpopulation AFR AF= 0.0264 (1094/41498). AF 95% confidence interval is 0.0251. There are 18 homozygotes in gnomad4. There are 562 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 1131 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GREB1L	NM_001142966.3	c.-7G>A		splice_region_variant, 5_prime_UTR_variant	3/33	ENST00000424526.7
LOC101927521	XR_001753366.2	n.245-2837C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GREB1L	ENST00000424526.7	c.-7G>A		splice_region_variant, 5_prime_UTR_variant	3/33	5	NM_001142966.3
	ENST00000584611.1	n.290-2837C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00744 AC: 1131 AN: 152014 Hom.: 18 Cov.: 31

Gnomad AFR AF: 0.0263

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00169 AC: 231 AN: 136594 Hom.: 1 AF XY: 0.00127 AC XY: 92 AN XY: 72272

Gnomad AFR exome AF: 0.0272

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000520

GnomAD4 exome AF: 0.000689 AC: 950 AN: 1378588 Hom.: 11 Cov.: 30 AF XY: 0.000548 AC XY: 372 AN XY: 679350

Gnomad4 AFR exome AF: 0.0268

Gnomad4 AMR exome AF: 0.00128

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000268

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000373

Gnomad4 OTH exome AF: 0.00163

GnomAD4 genome AF: 0.00747 AC: 1137 AN: 152132 Hom.: 18 Cov.: 31 AF XY: 0.00755 AC XY: 562 AN XY: 74390

Gnomad4 AFR AF: 0.0264

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00417 Hom.: 2

Bravo AF: 0.00832

Asia WGS AF: 0.00115 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

GREB1L-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 01, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	1.4
Dann	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.012
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: rs73432789; hg19: chr18-18963473;