Genetic Variant NM_022139.4:c.*499G>A (chr20-3659410-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_022139.4(GFRA4):c.*499G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.549 in 164,374 control chromosomes in the GnomAD database, including 27,218 homozygotes. 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: 𝑓 0.54 ( 24328 hom., cov: 33)

Exomes 𝑓: 0.68 ( 2890 hom. )

Consequence

GFRA4
NM_022139.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.225

Publications

9 publications found

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 was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.67 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022139.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFRA4	NM_022139.4	MANE Select	c.*499G>A		3_prime_UTR	Exon 6 of 6	NP_071422.1	Q9GZZ7-2
	GFRA4	NM_145762.3		c.*499G>A		3_prime_UTR	Exon 5 of 5	NP_665705.1	Q9GZZ7-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GFRA4	ENST00000290417.7	TSL:1 MANE Select	c.*499G>A	3_prime_UTR	Exon 6 of 6	ENSP00000290417.2	Q9GZZ7-2
GFRA4	ENST00000319242.8	TSL:1	c.*499G>A	3_prime_UTR	Exon 5 of 5	ENSP00000313423.3	Q9GZZ7-1
GFRA4	ENST00000850978.1		c.*499G>A	3_prime_UTR	Exon 6 of 6	ENSP00000521061.1

Frequencies

GnomAD3 genomes

AF:

0.539

AC:

81885

AN:

151990

Hom.:

24316

Cov.:

show subpopulations

Gnomad AFR

AF:

0.278

Gnomad AMI

AF:

0.703

Gnomad AMR

AF:

0.578

Gnomad ASJ

AF:

0.624

Gnomad EAS

AF:

0.464

Gnomad SAS

AF:

0.631

Gnomad FIN

AF:

0.579

Gnomad MID

AF:

0.519

Gnomad NFE

AF:

0.675

Gnomad OTH

AF:

0.540

GnomAD4 exome

AF:

0.681

AC:

8351

AN:

12266

Hom.:

2890

Cov.:

AF XY:

0.681

AC XY:

4412

AN XY:

6476

show subpopulations

African (AFR)

AF:

0.417

AC:

AN:

American (AMR)

AF:

0.611

AC:

1220

AN:

1998

Ashkenazi Jewish (ASJ)

AF:

0.686

AC:

140

AN:

204

East Asian (EAS)

AF:

0.539

AC:

AN:

102

South Asian (SAS)

AF:

0.665

AC:

1126

AN:

1694

European-Finnish (FIN)

AF:

0.688

AC:

249

AN:

362

Middle Eastern (MID)

AF:

0.500

AC:

AN:

European-Non Finnish (NFE)

AF:

0.712

AC:

5130

AN:

7204

Other (OTH)

AF:

0.647

AC:

378

AN:

584

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.527

Heterozygous variant carriers

131

262

392

523

654

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

216

288

360

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.539

AC:

81937

AN:

152108

Hom.:

24328

Cov.:

AF XY:

0.537

AC XY:

39912

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.278

AC:

11530

AN:

41472

American (AMR)

AF:

0.578

AC:

8846

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.624

AC:

2166

AN:

3470

East Asian (EAS)

AF:

0.464

AC:

2394

AN:

5162

South Asian (SAS)

AF:

0.632

AC:

3042

AN:

4812

European-Finnish (FIN)

AF:

0.579

AC:

6131

AN:

10584

Middle Eastern (MID)

AF:

0.531

AC:

156

AN:

294

European-Non Finnish (NFE)

AF:

0.675

AC:

45890

AN:

68000

Other (OTH)

AF:

0.541

AC:

1141

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1762

3524

5287

7049

8811

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

704

1408

2112

2816

3520

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.626

Hom.:

112034

Bravo

AF:

0.527

Asia WGS

AF:

0.546

AC:

1900

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

5.6

(source)

DANN

Benign

0.46

PhyloP100

0.23

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over