dbSNP rs75841238: GFRA1:p.Leu448Leu (chr10-116064452-C-G) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBP7

The NM_005264.8(GFRA1):c.1344G>C(p.Leu448Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000546 in 1,612,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00056 ( 0 hom. )

Consequence

GFRA1
NM_005264.8 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.40

Publications

0 publications found

Variant links:

Genes affected

GFRA1 (HGNC:4243): (GDNF family receptor alpha 1) This gene encodes a member of the glial cell line-derived neurotrophic factor receptor (GDNFR) family of proteins. The encoded preproprotein is proteolytically processed to generate the mature receptor. 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. This receptor is a glycosylphosphatidylinositol (GPI)-linked cell surface receptor for both GDNF and NTN, and mediates activation of the RET tyrosine kinase receptor. This gene is a candidate gene for Hirschsprung disease. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed. [provided by RefSeq, Jan 2016]

GFRA1 Gene-Disease associations (from GenCC):

renal hypodysplasia/aplasia 4
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

GFRA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant 10-116064452-C-G is Benign according to our data. Variant chr10-116064452-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 776768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.4 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005264.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GFRA1	NM_005264.8	MANE Select	c.1344G>C	p.Leu448Leu	synonymous	Exon 11 of 11	NP_005255.1	P56159-1
GFRA1	NM_001348098.4		c.1344G>C	p.Leu448Leu	synonymous	Exon 11 of 11	NP_001335027.1	P56159-1
GFRA1	NM_001145453.4		c.1329G>C	p.Leu443Leu	synonymous	Exon 10 of 10	NP_001138925.1	P56159-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GFRA1	ENST00000355422.11	TSL:5 MANE Select	c.1344G>C	p.Leu448Leu	synonymous	Exon 11 of 11	ENSP00000347591.6	P56159-1
GFRA1	ENST00000369236.5	TSL:1	c.1329G>C	p.Leu443Leu	synonymous	Exon 9 of 9	ENSP00000358239.1	P56159-2
GFRA1	ENST00000369234.5	TSL:5	c.1344G>C	p.Leu448Leu	synonymous	Exon 11 of 11	ENSP00000358237.4	P56159-1

Frequencies

GnomAD3 genomes

AF:

0.000369

AC:

AN:

151926

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000750

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000275

AC:

AN:

251084

AF XY:

0.000280

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000547

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000564

AC:

824

AN:

1460912

Hom.:

Cov.:

AF XY:

0.000557

AC XY:

405

AN XY:

726802

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33458

American (AMR)

AF:

0.0000671

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86226

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5418

European-Non Finnish (NFE)

AF:

0.000713

AC:

792

AN:

1111534

Other (OTH)

AF:

0.000414

AC:

AN:

60324

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

123

164

205

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

102

136

170

<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:

0.000369

AC:

AN:

151926

Hom.:

Cov.:

AF XY:

0.000324

AC XY:

AN XY:

74158

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41360

American (AMR)

AF:

0.00

AC:

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4774

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000750

AC:

AN:

67992

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000580

Hom.:

Bravo

AF:

0.000298

EpiCase

AF:

0.000436

EpiControl

AF:

0.000533

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

9.3

(source)

DANN

Benign

0.80

PhyloP100

1.4

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

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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