chr10-116125439-G-A

Variant names:

• chr10-116125439-G-A
• rs2245020
• NM_005264.8:c.552C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_005264.8(GFRA1):​c.552C>T​(p.Asn184Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.555 in 1,613,566 control chromosomes in the GnomAD database, including 252,262 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.50 (20162 hom., cov: 34)
  • Exomes 𝑓: 0.56 (232100 hom.)
• Consequence: GFRA1 NM_005264.8 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.282
• Publications: 26 publications found

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]

GFRA1 Gene-Disease associations (from GenCC):

• renal hypodysplasia/aplasia 4

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 10-116125439-G-A is Benign according to our data. Variant chr10-116125439-G-A is described in ClinVar as Benign. ClinVar VariationId is 3060424.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-0.282 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.615 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005264.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFRA1	NM_005264.8	MANE Select	c.552C>T	p.Asn184Asn	synonymous	Exon 6 of 11	NP_005255.1
	GFRA1	NM_001348098.4		c.552C>T	p.Asn184Asn	synonymous	Exon 6 of 11	NP_001335027.1
	GFRA1	NM_001145453.4		c.537C>T	p.Asn179Asn	synonymous	Exon 5 of 10	NP_001138925.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFRA1	ENST00000355422.11	TSL:5 MANE Select	c.552C>T	p.Asn184Asn	synonymous	Exon 6 of 11	ENSP00000347591.6
	GFRA1	ENST00000369236.5	TSL:1	c.537C>T	p.Asn179Asn	synonymous	Exon 4 of 9	ENSP00000358239.1
	GFRA1	ENST00000369234.5	TSL:5	c.552C>T	p.Asn184Asn	synonymous	Exon 6 of 11	ENSP00000358237.4

Frequencies

GnomAD3 genomes AF: 0.498 AC: 75653 AN: 151998 Hom.: 20153 Cov.: 34

Gnomad AFR AF: 0.302

Gnomad AMI AF: 0.626

Gnomad AMR AF: 0.625

Gnomad ASJ AF: 0.562

Gnomad EAS AF: 0.573

Gnomad SAS AF: 0.558

Gnomad FIN AF: 0.571

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.561

Gnomad OTH AF: 0.525

GnomAD2 exomes AF: 0.568 AC: 142471 AN: 250954 AF XY: 0.568

Gnomad AFR exome AF: 0.304

Gnomad AMR exome AF: 0.701

Gnomad ASJ exome AF: 0.578

Gnomad EAS exome AF: 0.585

Gnomad FIN exome AF: 0.572

Gnomad NFE exome AF: 0.563

Gnomad OTH exome AF: 0.566

GnomAD4 exome AF: 0.561 AC: 819886 AN: 1461448 Hom.: 232100 Cov.: 55 AF XY: 0.561 AC XY: 407684 AN XY: 727026

African (AFR) AF: 0.300 AC: 10055 AN: 33474

American (AMR) AF: 0.693 AC: 30996 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.570 AC: 14884 AN: 26132

East Asian (EAS) AF: 0.568 AC: 22535 AN: 39692

South Asian (SAS) AF: 0.555 AC: 47889 AN: 86250

European-Finnish (FIN) AF: 0.575 AC: 30684 AN: 53384

Middle Eastern (MID) AF: 0.563 AC: 3246 AN: 5766

European-Non Finnish (NFE) AF: 0.563 AC: 626302 AN: 1111664

Other (OTH) AF: 0.551 AC: 33295 AN: 60380

GnomAD4 genome AF: 0.498 AC: 75682 AN: 152118 Hom.: 20162 Cov.: 34 AF XY: 0.502 AC XY: 37299 AN XY: 74350

African (AFR) AF: 0.301 AC: 12497 AN: 41514

American (AMR) AF: 0.626 AC: 9575 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.562 AC: 1952 AN: 3472

East Asian (EAS) AF: 0.573 AC: 2946 AN: 5138

South Asian (SAS) AF: 0.559 AC: 2694 AN: 4820

European-Finnish (FIN) AF: 0.571 AC: 6042 AN: 10580

Middle Eastern (MID) AF: 0.565 AC: 165 AN: 292

European-Non Finnish (NFE) AF: 0.561 AC: 38132 AN: 67984

Other (OTH) AF: 0.527 AC: 1112 AN: 2112

Alfa AF: 0.536 Hom.: 34913

Bravo AF: 0.494

Asia WGS AF: 0.564 AC: 1960 AN: 3478

EpiCase AF: 0.565

EpiControl AF: 0.557

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	GFRA1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	1.1
DANN	Benign	0.91
PhyloP100		-0.28
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2245020; hg19: chr10-117884950; COSMIC: COSV62603718;