10-116125244-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_005264.8(GFRA1):c.747C>T(p.Ser249=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0056 in 1,614,140 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0057 (28 hom.)
• Consequence: GFRA1 NM_005264.8 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.19

Genes affected

GFRA1 (HGNC:4243): (GDNF family receptor alpha 1) This gene encodes a member of the glial cell line-derived neurotrophic factor receptor (GDNFR) family of proteins. The encoded preproprotein is proteolytically processed to generate the mature receptor. Glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN) are two structurally related, potent neurotrophic factors that play key roles in the control of neuron survival and differentiation. This receptor is a glycosylphosphatidylinositol (GPI)-linked cell surface receptor for both GDNF and NTN, and mediates activation of the RET tyrosine kinase receptor. This gene is a candidate gene for Hirschsprung disease. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 10-116125244-G-A is Benign according to our data. Variant chr10-116125244-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 784518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.19 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GFRA1	NM_005264.8	c.747C>T	p.Ser249=	synonymous_variant	6/11	ENST00000355422.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFRA1	ENST00000355422.11	c.747C>T	p.Ser249=	synonymous_variant	6/11	5	NM_005264.8	A2

Frequencies

GnomAD3 genomes AF: 0.00507 AC: 772 AN: 152188 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000844

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00766

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.0155

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00620

Gnomad OTH AF: 0.00716

GnomAD3 exomes AF: 0.00526 AC: 1321 AN: 251232 Hom.: 7 AF XY: 0.00510 AC XY: 693 AN XY: 135810

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.00350

Gnomad ASJ exome AF: 0.00566

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.0154

Gnomad NFE exome AF: 0.00664

Gnomad OTH exome AF: 0.00506

GnomAD4 exome AF: 0.00565 AC: 8266 AN: 1461834 Hom.: 28 Cov.: 32 AF XY: 0.00547 AC XY: 3980 AN XY: 727214

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.00356

Gnomad4 ASJ exome AF: 0.00539

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000533

Gnomad4 FIN exome AF: 0.0152

Gnomad4 NFE exome AF: 0.00610

Gnomad4 OTH exome AF: 0.00465

GnomAD4 genome AF: 0.00507 AC: 772 AN: 152306 Hom.: 3 Cov.: 33 AF XY: 0.00530 AC XY: 395 AN XY: 74472

Gnomad4 AFR AF: 0.000841

Gnomad4 AMR AF: 0.00765

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.0155

Gnomad4 NFE AF: 0.00620

Gnomad4 OTH AF: 0.00709

Alfa AF: 0.00544 Hom.: 1

Bravo AF: 0.00417

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00567

EpiControl AF: 0.00682

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	GFRA1: BP4, BP7, BS2 -

GFRA1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 24, 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	-0.48
Cadd	Benign	8.0
Dann	Benign	0.79

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: rs76248338; hg19: chr10-117884755;