Genetic Variant GFRA1:c.*5349C>T (chr10-116059049-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005264.8(GFRA1):c.*5349C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.404 in 152,064 control chromosomes in the GnomAD database, including 15,326 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.40 ( 15324 hom., cov: 32)

Exomes 𝑓: 0.36 ( 2 hom. )

Consequence

GFRA1
NM_005264.8 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -4.08

Publications

4 publications found

Variant links:

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

GFRA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.689 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFRA1	NM_005264.8 link	c.*5349C>T		3_prime_UTR_variant	Exon 11 of 11	ENST00000355422.11	NP_005255.1	P56159-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFRA1	ENST00000355422.11 link	c.*5349C>T		3_prime_UTR_variant	Exon 11 of 11	5	NM_005264.8	ENSP00000347591.6		P56159-1
GFRA1	ENST00000369236.5 link	c.*5349C>T		3_prime_UTR_variant	Exon 9 of 9	1		ENSP00000358239.1		P56159-2

Frequencies

GnomAD3 genomes

AF:

0.404

AC:

61343

AN:

151924

Hom.:

15285

Cov.:

show subpopulations

Gnomad AFR

AF:

0.695

Gnomad AMI

AF:

0.170

Gnomad AMR

AF:

0.357

Gnomad ASJ

AF:

0.209

Gnomad EAS

AF:

0.616

Gnomad SAS

AF:

0.352

Gnomad FIN

AF:

0.283

Gnomad MID

AF:

0.342

Gnomad NFE

AF:

0.257

Gnomad OTH

AF:

0.403

GnomAD4 exome

AF:

0.364

AC:

AN:

Hom.:

Cov.:

AF XY:

0.375

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.500

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.350

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.404

AC:

61429

AN:

152042

Hom.:

15324

Cov.:

AF XY:

0.405

AC XY:

30074

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.695

AC:

28829

AN:

41452

American (AMR)

AF:

0.357

AC:

5458

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.209

AC:

725

AN:

3466

East Asian (EAS)

AF:

0.616

AC:

3178

AN:

5162

South Asian (SAS)

AF:

0.352

AC:

1698

AN:

4824

European-Finnish (FIN)

AF:

0.283

AC:

2981

AN:

10548

Middle Eastern (MID)

AF:

0.344

AC:

101

AN:

294

European-Non Finnish (NFE)

AF:

0.257

AC:

17449

AN:

67980

Other (OTH)

AF:

0.404

AC:

855

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1617

3235

4852

6470

8087

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.303

Hom.:

9932

Bravo

AF:

0.424

Asia WGS

AF:

0.488

AC:

1694

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.016

(source)

DANN

Benign

0.58

PhyloP100

-4.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

chr10-116059049-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over