chr8-21693346-G-A

Position:

• chr8-21693346-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001495.5(GFRA2):​c.1327C>T​(p.Pro443Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00232 in 1,613,242 control chromosomes in the GnomAD database, including 85 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (9 hom., cov: 31)
  • Exomes 𝑓: 0.0023 (76 hom.)
• Consequence: GFRA2 NM_001495.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.215

Genes affected

GFRA2 (HGNC:4244): (GDNF family receptor alpha 2) 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. The protein encoded by this gene is a member of the GDNF receptor family. It is a glycosylphosphatidylinositol(GPI)-linked cell surface receptor for both GDNF and NTN, and mediates activation of the RET tyrosine kinase receptor. This encoded protein acts preferentially as a receptor for NTN compared to its other family member, GDNF family receptor alpha 1. This gene is a candidate gene for RET-associated diseases. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016376376).
• BP6: Variant 8-21693346-G-A is Benign according to our data. Variant chr8-21693346-G-A is described in ClinVar as [Benign]. Clinvar id is 708036.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0533 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GFRA2	NM_001495.5	c.1327C>T	p.Pro443Ser	missense_variant	9/9	ENST00000524240.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFRA2	ENST00000524240.6	c.1327C>T	p.Pro443Ser	missense_variant	9/9	1	NM_001495.5	P1

Frequencies

GnomAD3 genomes AF: 0.00281 AC: 428 AN: 152076 Hom.: 9 Cov.: 31

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.0590

Gnomad SAS AF: 0.00415

Gnomad FIN AF: 0.00434

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00640 AC: 1574 AN: 246126 Hom.: 45 AF XY: 0.00602 AC XY: 805 AN XY: 133780

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.0000584

Gnomad ASJ exome AF: 0.000798

Gnomad EAS exome AF: 0.0714

Gnomad SAS exome AF: 0.00302

Gnomad FIN exome AF: 0.00427

Gnomad NFE exome AF: 0.000733

Gnomad OTH exome AF: 0.00316

GnomAD4 exome AF: 0.00226 AC: 3308 AN: 1461048 Hom.: 76 Cov.: 32 AF XY: 0.00239 AC XY: 1735 AN XY: 726778

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.0000896

Gnomad4 ASJ exome AF: 0.000765

Gnomad4 EAS exome AF: 0.0557

Gnomad4 SAS exome AF: 0.00304

Gnomad4 FIN exome AF: 0.00532

Gnomad4 NFE exome AF: 0.000309

Gnomad4 OTH exome AF: 0.00297

GnomAD4 genome AF: 0.00281 AC: 428 AN: 152194 Hom.: 9 Cov.: 31 AF XY: 0.00329 AC XY: 245 AN XY: 74406

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.0587

Gnomad4 SAS AF: 0.00436

Gnomad4 FIN AF: 0.00434

Gnomad4 NFE AF: 0.000647

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00154 Hom.: 5

Bravo AF: 0.00295

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00615 AC: 743

Asia WGS AF: 0.0280 AC: 97 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000534

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 24, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	12
DANN	Benign	0.43
DEOGEN2	Benign	0.061	T;T;.;.
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.71	.;T;T;T
MetaRNN	Benign	0.0016	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.83	N;N;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.60	N;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.45	T;T;T;T
Sift4G	Benign	0.93	T;T;T;T
Polyphen		0.0	B;B;B;.
Vest4		0.036
MVP		0.28
MPC		0.021
ClinPred		0.0035	T
GERP RS		1.2
Varity_R		0.023
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs77601365; hg19: chr8-21550858; COSMIC: COSV60780318;