20-3660813-G-C

Position:

• chr20-3660813-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_145762.3(GFRA4):​c.523C>G​(p.Arg175Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000158 in 1,264,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: GFRA4 NM_145762.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0600

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14824662).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFRA4	NM_022139.4	c.444C>G	p.Pro148Pro	synonymous_variant	3/6	ENST00000290417.7	NP_071422.1
GFRA4	NM_145762.3	c.523C>G	p.Arg175Gly	missense_variant	2/5		NP_665705.1
GFRA4	XM_005260793.2	c.444C>G	p.Pro148Pro	synonymous_variant	3/4		XP_005260850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFRA4	ENST00000319242.8	c.523C>G	p.Arg175Gly	missense_variant	2/5	1		ENSP00000313423.3
GFRA4	ENST00000290417.7	c.444C>G	p.Pro148Pro	synonymous_variant	3/6	1	NM_022139.4	ENSP00000290417.2
GFRA4	ENST00000477160.1	n.444C>G		non_coding_transcript_exon_variant	3/4	1		ENSP00000435801.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000158 AC: 2 AN: 1264102 Hom.: 0 Cov.: 39 AF XY: 0.00000162 AC XY: 1 AN XY: 616666

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: 9.71e-7

Gnomad4 OTH exome AF: 0.0000192

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 06, 2021

The c.523C>G (p.R175G) alteration is located in exon 2 (coding exon 2) of the GFRA4 gene. This alteration results from a C to G substitution at nucleotide position 523, causing the arginine (R) at amino acid position 175 to be replaced by a glycine (G). 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	0.097
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	4.6
DANN	Uncertain	0.99
DEOGEN2	Benign	0.091	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.32	T
M_CAP	Pathogenic	0.78	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.038
Sift	Benign	0.49	T
Sift4G	Benign	0.69	T
Polyphen		0.0060	B
Vest4		0.090
MutPred		0.27		Loss of solvent accessibility (P = 0.0329);
MVP		0.60
MPC		0.51
ClinPred		0.16	T
GERP RS		-0.61
Varity_R		0.11
gMVP		0.43

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.

Other links and lift over

hg19: chr20-3641460;