Variant 20-3660619-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_022139.4(GFRA4):c.544C>T(p.Arg182Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000357 in 1,398,898 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)

Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

GFRA4
NM_022139.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.52

Variant links:

Genes affected

GFRA4 (HGNC:13821): (GDNF family receptor alpha 4) The protein encoded by this gene is a member of the GDNF receptor family. It is a glycosylphosphatidylinositol(GPI)-linked cell surface receptor for persephin, and mediates activation of the RET tyrosine kinase receptor. This gene is a candidate gene for RET-associated diseases. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

GFRA4 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.29320467).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFRA4	NM_022139.4 linkuse as main transcript	c.544C>T	p.Arg182Cys	missense_variant	4/6	ENST00000290417.7	NP_071422.1	Q9GZZ7-2
GFRA4	NM_145762.3 linkuse as main transcript	c.634C>T	p.Arg212Cys	missense_variant	3/5		NP_665705.1	Q9GZZ7-1
GFRA4	XM_005260793.2 linkuse as main transcript	c.*6C>T		3_prime_UTR_variant	4/4		XP_005260850.1	Q9GZZ7-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
GFRA4	ENST00000290417.7 linkuse as main transcript	c.544C>T	p.Arg182Cys	missense_variant	4/6	1	NM_022139.4	ENSP00000290417.2	Q9GZZ7-2
GFRA4	ENST00000319242.8 linkuse as main transcript	c.634C>T	p.Arg212Cys	missense_variant	3/5	1		ENSP00000313423.3	Q9GZZ7-1
GFRA4	ENST00000477160.1 linkuse as main transcript	n.*6C>T		downstream_gene_variant		1		ENSP00000435801.1	Q9GZZ7-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000205

AC:

AN:

146502

Hom.:

AF XY:

0.0000253

AC XY:

AN XY:

79018

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000811

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000188

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000357

AC:

AN:

1398898

Hom.:

Cov.:

AF XY:

0.00000435

AC XY:

AN XY:

690064

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000557

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:

0.00000278

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000283

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2024

The c.634C>T (p.R212C) alteration is located in exon 3 (coding exon 3) of the GFRA4 gene. This alteration results from a C to T substitution at nucleotide position 634, causing the arginine (R) at amino acid position 212 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Benign

-0.00064

BayesDel_noAF

Benign

-0.24

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

.;T

Eigen

Benign

0.16

Eigen_PC

Benign

0.11

FATHMM_MKL

Benign

0.24

LIST_S2

Uncertain

0.94

D;D

M_CAP

Benign

0.016

MetaRNN

Benign

0.29

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

.;L

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-2.9

D;D

REVEL

Benign

0.13

Sift

Benign

0.043

D;D

Sift4G

Uncertain

0.022

D;D

Polyphen

1.0

D;D

Vest4

0.45

MutPred

0.53

.;Loss of disorder (P = 0.0804);

MVP

0.58

MPC

1.1

ClinPred

0.84

GERP RS

4.0

Varity_R

0.17

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over