Variant 20-3660990-A-G 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.346T>C(p.Ser116Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GFRA4
NM_022139.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.25

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=0.2912864).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
GFRA4	NM_022139.4 linkuse as main transcript	c.346T>C	p.Ser116Pro	missense_variant	2/6	ENST00000290417.7
GFRA4	NM_145762.3 linkuse as main transcript	c.346T>C	p.Ser116Pro	missense_variant	2/5
GFRA4	XM_005260793.2 linkuse as main transcript	c.346T>C	p.Ser116Pro	missense_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFRA4	ENST00000290417.7 linkuse as main transcript	c.346T>C	p.Ser116Pro	missense_variant	2/6	1	NM_022139.4	P1	Q9GZZ7-2
GFRA4	ENST00000319242.8 linkuse as main transcript	c.346T>C	p.Ser116Pro	missense_variant	2/5	1			Q9GZZ7-1
GFRA4	ENST00000477160.1 linkuse as main transcript	c.346T>C	p.Ser116Pro	missense_variant, NMD_transcript_variant	2/4	1			Q9GZZ7-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1154604

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

569346

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Feb 27, 2024

The c.346T>C (p.S116P) alteration is located in exon 2 (coding exon 2) of the GFRA4 gene. This alteration results from a T to C substitution at nucleotide position 346, causing the serine (S) at amino acid position 116 to be replaced by a proline (P). 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

Uncertain

0.43

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Uncertain

0.98

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.24

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.41

T;T

M_CAP

Pathogenic

0.62

MetaRNN

Benign

0.29

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.7

L;L

MutationTaster

Benign

0.76

N;N

PrimateAI

Pathogenic

0.79

PROVEAN

Uncertain

-3.0

D;D

REVEL

Benign

0.080

Sift

Benign

0.049

D;T

Sift4G

Uncertain

0.022

D;D

Polyphen

0.047

B;B

Vest4

0.22

MutPred

0.24

Gain of catalytic residue at S116 (P = 0.0107);Gain of catalytic residue at S116 (P = 0.0107);

MVP

0.38

MPC

0.40

ClinPred

0.57

GERP RS

2.1

Varity_R

0.38

gMVP

0.80

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over