18-21383541-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP5_Moderate

The NM_001142966.3(GREB1L):c.23A>C(p.Gln8Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000324 in 1,541,202 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: GREB1L NM_001142966.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.95

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, GREB1L
• PP5: Variant 18-21383541-A-C is Pathogenic according to our data. Variant chr18-21383541-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2690950.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GREB1L	NM_001142966.3	c.23A>C	p.Gln8Pro	missense_variant	3/33	ENST00000424526.7
LOC101927521	XR_001753366.2	n.245-2866T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GREB1L	ENST00000424526.7	c.23A>C	p.Gln8Pro	missense_variant	3/33	5	NM_001142966.3
	ENST00000584611.1	n.290-2866T>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000133 AC: 2 AN: 150692 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000296

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000216 AC: 3 AN: 1390510 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 685436

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000186

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome AF: 0.0000133 AC: 2 AN: 150692 Hom.: 0 Cov.: 31 AF XY: 0.0000136 AC XY: 1 AN XY: 73580

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000296

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000660 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Male infertility with azoospermia or oligozoospermia due to single gene mutation Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Laan Lab, Human Genetics Research Group, University of Tartu

Sep 01, 2023

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Benign	0.025	T;.;T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;.
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.70	D;D;D
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.9	L;L;L
MutationTaster	Benign	0.97	D;D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-4.4	D;D;.
REVEL	Uncertain	0.48
Sift	Uncertain	0.0020	D;D;.
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.77
MutPred		0.32		Gain of relative solvent accessibility (P = 0.0215);Gain of relative solvent accessibility (P = 0.0215);Gain of relative solvent accessibility (P = 0.0215);
MVP		0.34
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.70
gMVP		0.62

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: rs1212136611; hg19: chr18-18963502; COSMIC: COSV52568915;