Variant chr20-3661106-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_022139.4(GFRA4):c.230C>T(p.Pro77Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000236 in 1,313,370 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000022 ( 1 hom. )

Consequence

GFRA4
NM_022139.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.03

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFRA4	NM_022139.4 linkuse as main transcript	c.230C>T	p.Pro77Leu	missense_variant	2/6	ENST00000290417.7	NP_071422.1	Q9GZZ7-2
GFRA4	NM_145762.3 linkuse as main transcript	c.230C>T	p.Pro77Leu	missense_variant	2/5		NP_665705.1	Q9GZZ7-1
GFRA4	XM_005260793.2 linkuse as main transcript	c.230C>T	p.Pro77Leu	missense_variant	2/4		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.230C>T	p.Pro77Leu	missense_variant	2/6	1	NM_022139.4	ENSP00000290417.2	Q9GZZ7-2
GFRA4	ENST00000319242.8 linkuse as main transcript	c.230C>T	p.Pro77Leu	missense_variant	2/5	1		ENSP00000313423.3	Q9GZZ7-1
GFRA4	ENST00000477160.1 linkuse as main transcript	n.230C>T		non_coding_transcript_exon_variant	2/4	1		ENSP00000435801.1	Q9GZZ7-3

Frequencies

GnomAD3 genomes

AF:

0.0000396

AC:

AN:

151504

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000215

AC:

AN:

1161758

Hom.:

Cov.:

AF XY:

0.0000249

AC XY:

AN XY:

562200

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000799

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000103

Gnomad4 OTH exome

AF:

0.0000637

GnomAD4 genome

AF:

0.0000396

AC:

AN:

151612

Hom.:

Cov.:

AF XY:

0.0000540

AC XY:

AN XY:

74104

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00117

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000491

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

Mar 20, 2024

The c.230C>T (p.P77L) alteration is located in exon 2 (coding exon 2) of the GFRA4 gene. This alteration results from a C to T substitution at nucleotide position 230, causing the proline (P) at amino acid position 77 to be replaced by a leucine (L). 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

Benign

0.28

BayesDel_addAF

Benign

-0.031

BayesDel_noAF

Benign

-0.28

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

.;T

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.75

T;T

M_CAP

Pathogenic

0.96

MetaRNN

Uncertain

0.65

D;D

MetaSVM

Benign

-0.32

MutationAssessor

Uncertain

2.5

M;M

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-5.1

D;D

REVEL

Benign

0.28

Sift

Uncertain

0.0080

D;D

Sift4G

Uncertain

0.0090

D;D

Polyphen

1.0

D;D

Vest4

0.33

MutPred

0.45

Loss of catalytic residue at P76 (P = 0.0185);Loss of catalytic residue at P76 (P = 0.0185);

MVP

0.87

MPC

1.0

ClinPred

0.98

GERP RS

4.3

Varity_R

0.26

gMVP

0.73

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

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