NM_005264.8:c.*5349C>T

Variant names:

• chr10-116059049-G-A
• rs180554
• NM_005264.8:c.*5349C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005264.8(GFRA1):​c.*5349C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.404 in 152,064 control chromosomes in the GnomAD database, including 15,326 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 0.40 (15324 hom., cov: 32)
  • Exomes 𝑓: 0.36 (2 hom.)
• Consequence: GFRA1 NM_005264.8 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.08
• Publications: 4 publications found

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: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.689 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFRA1	NM_005264.8	MANE Select	c.*5349C>T		3_prime_UTR	Exon 11 of 11	NP_005255.1	P56159-1
	GFRA1	NM_001348098.4		c.*5349C>T		3_prime_UTR	Exon 11 of 11	NP_001335027.1	P56159-1
	GFRA1	NM_001145453.4		c.*5349C>T		3_prime_UTR	Exon 10 of 10	NP_001138925.1	P56159-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFRA1	ENST00000355422.11	TSL:5 MANE Select	c.*5349C>T		3_prime_UTR	Exon 11 of 11	ENSP00000347591.6	P56159-1
	GFRA1	ENST00000369236.5	TSL:1	c.*5349C>T		3_prime_UTR	Exon 9 of 9	ENSP00000358239.1	P56159-2

Frequencies

GnomAD3 genomes AF: 0.404 AC: 61343 AN: 151924 Hom.: 15285 Cov.: 32

Gnomad AFR AF: 0.695

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.357

Gnomad ASJ AF: 0.209

Gnomad EAS AF: 0.616

Gnomad SAS AF: 0.352

Gnomad FIN AF: 0.283

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.257

Gnomad OTH AF: 0.403

GnomAD4 exome AF: 0.364 AC: 8 AN: 22 Hom.: 2 Cov.: 0 AF XY: 0.375 AC XY: 6 AN XY: 16

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.500 AC: 1 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.350 AC: 7 AN: 20

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.404 AC: 61429 AN: 152042 Hom.: 15324 Cov.: 32 AF XY: 0.405 AC XY: 30074 AN XY: 74320

African (AFR) AF: 0.695 AC: 28829 AN: 41452

American (AMR) AF: 0.357 AC: 5458 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.209 AC: 725 AN: 3466

East Asian (EAS) AF: 0.616 AC: 3178 AN: 5162

South Asian (SAS) AF: 0.352 AC: 1698 AN: 4824

European-Finnish (FIN) AF: 0.283 AC: 2981 AN: 10548

Middle Eastern (MID) AF: 0.344 AC: 101 AN: 294

European-Non Finnish (NFE) AF: 0.257 AC: 17449 AN: 67980

Other (OTH) AF: 0.404 AC: 855 AN: 2114

Alfa AF: 0.303 Hom.: 9932

Bravo AF: 0.424

Asia WGS AF: 0.488 AC: 1694 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.016
DANN	Benign	0.58
PhyloP100		-4.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs180554; hg19: chr10-117818560; COSMIC: COSV62609897; COSMIC: COSV62609897;