dbSNP rs1679568: GFRA1:c.*6358C>T (chr10-116058040-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.*6358C>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 0.224 in 141,356 control chromosomes in the GnomAD database, including 3,971 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 0.23 ( 3965 hom., cov: 29)

Exomes 𝑓: 0.038 ( 6 hom. )

Consequence

GFRA1
NM_005264.8 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.508

Publications

7 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=-0.82).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.341 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFRA1	NM_005264.8 link	c.*6358C>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.*6358C>T		3_prime_UTR_variant	Exon 11 of 11	5	NM_005264.8	ENSP00000347591.6		P56159-1
GFRA1	ENST00000369236.5 link	c.*6358C>T		3_prime_UTR_variant	Exon 9 of 9	1		ENSP00000358239.1		P56159-2

Frequencies

GnomAD3 genomes

AF:

0.225

AC:

31617

AN:

140252

Hom.:

3958

Cov.:

show subpopulations

Gnomad AFR

AF:

0.345

Gnomad AMI

AF:

0.131

Gnomad AMR

AF:

0.169

Gnomad ASJ

AF:

0.155

Gnomad EAS

AF:

0.174

Gnomad SAS

AF:

0.165

Gnomad FIN

AF:

0.191

Gnomad MID

AF:

0.243

Gnomad NFE

AF:

0.185

Gnomad OTH

AF:

0.231

GnomAD4 exome

AF:

0.0377

AC:

AN:

1008

Hom.:

Cov.:

AF XY:

0.0364

AC XY:

AN XY:

770

show subpopulations

African (AFR)

AF:

0.0714

AC:

AN:

American (AMR)

AF:

0.0500

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.0625

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0371

AC:

AN:

862

Other (OTH)

AF:

0.0500

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.226

AC:

31653

AN:

140348

Hom.:

3965

Cov.:

AF XY:

0.223

AC XY:

15218

AN XY:

68214

show subpopulations

African (AFR)

AF:

0.346

AC:

12948

AN:

37476

American (AMR)

AF:

0.169

AC:

2346

AN:

13912

Ashkenazi Jewish (ASJ)

AF:

0.155

AC:

496

AN:

3200

East Asian (EAS)

AF:

0.173

AC:

648

AN:

3736

South Asian (SAS)

AF:

0.166

AC:

714

AN:

4310

European-Finnish (FIN)

AF:

0.191

AC:

1859

AN:

9744

Middle Eastern (MID)

AF:

0.243

AC:

AN:

272

European-Non Finnish (NFE)

AF:

0.185

AC:

12010

AN:

64846

Other (OTH)

AF:

0.230

AC:

448

AN:

1952

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.521

Heterozygous variant carriers

1104

2208

3312

4416

5520

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.85

(source)

DANN

Benign

0.45

PhyloP100

0.51

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

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rs1679568

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