chr10-116270903-A-T

Variant names:

• chr10-116270903-A-T
• rs8192662
• NM_005264.8:c.253T>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005264.8(GFRA1):​c.253T>A​(p.Tyr85Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0303 in 1,614,030 control chromosomes in the GnomAD database, including 875 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.024 (56 hom., cov: 33)
  • Exomes 𝑓: 0.031 (819 hom.)
• Consequence: GFRA1 NM_005264.8 missense
• Clinical Significance: Benign criteria provided, single submitter B:4
• Conservation: PhyloP100: 7.19
• Publications: 12 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008683264).
• BP6: Variant 10-116270903-A-T is Benign according to our data. Variant chr10-116270903-A-T is described in ClinVar as Benign. ClinVar VariationId is 1328035.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0239 (3647/152336) while in subpopulation SAS AF = 0.0366 (177/4832). AF 95% confidence interval is 0.0322. There are 56 homozygotes in GnomAd4. There are 1886 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 56 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFRA1	NM_005264.8	MANE Select	c.253T>A	p.Tyr85Asn	missense	Exon 3 of 11	NP_005255.1
	GFRA1	NM_001348098.4		c.253T>A	p.Tyr85Asn	missense	Exon 3 of 11	NP_001335027.1
	GFRA1	NM_001145453.4		c.253T>A	p.Tyr85Asn	missense	Exon 3 of 10	NP_001138925.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFRA1	ENST00000355422.11	TSL:5 MANE Select	c.253T>A	p.Tyr85Asn	missense	Exon 3 of 11	ENSP00000347591.6
	GFRA1	ENST00000369236.5	TSL:1	c.253T>A	p.Tyr85Asn	missense	Exon 2 of 9	ENSP00000358239.1
	GFRA1	ENST00000369234.5	TSL:5	c.253T>A	p.Tyr85Asn	missense	Exon 3 of 11	ENSP00000358237.4

Frequencies

GnomAD3 genomes AF: 0.0240 AC: 3649 AN: 152218 Hom.: 56 Cov.: 33

Gnomad AFR AF: 0.00620

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0286

Gnomad ASJ AF: 0.0245

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0364

Gnomad FIN AF: 0.0493

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0311

Gnomad OTH AF: 0.0205

GnomAD2 exomes AF: 0.0274 AC: 6889 AN: 251248 AF XY: 0.0292

Gnomad AFR exome AF: 0.00560

Gnomad AMR exome AF: 0.0175

Gnomad ASJ exome AF: 0.0200

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.0514

Gnomad NFE exome AF: 0.0303

Gnomad OTH exome AF: 0.0280

GnomAD4 exome AF: 0.0310 AC: 45270 AN: 1461694 Hom.: 819 Cov.: 33 AF XY: 0.0314 AC XY: 22805 AN XY: 727156

African (AFR) AF: 0.00526 AC: 176 AN: 33476

American (AMR) AF: 0.0187 AC: 836 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0193 AC: 504 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.0414 AC: 3568 AN: 86256

European-Finnish (FIN) AF: 0.0458 AC: 2443 AN: 53284

Middle Eastern (MID) AF: 0.0284 AC: 164 AN: 5768

European-Non Finnish (NFE) AF: 0.0322 AC: 35754 AN: 1111956

Other (OTH) AF: 0.0301 AC: 1820 AN: 60394

GnomAD4 genome AF: 0.0239 AC: 3647 AN: 152336 Hom.: 56 Cov.: 33 AF XY: 0.0253 AC XY: 1886 AN XY: 74492

African (AFR) AF: 0.00618 AC: 257 AN: 41596

American (AMR) AF: 0.0286 AC: 438 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0245 AC: 85 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.0366 AC: 177 AN: 4832

European-Finnish (FIN) AF: 0.0493 AC: 524 AN: 10624

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0311 AC: 2118 AN: 68022

Other (OTH) AF: 0.0198 AC: 42 AN: 2116

Alfa AF: 0.0280 Hom.: 30

Bravo AF: 0.0205

TwinsUK AF: 0.0345 AC: 128

ALSPAC AF: 0.0361 AC: 139

ESP6500AA AF: 0.00794 AC: 35

ESP6500EA AF: 0.0324 AC: 279

ExAC AF: 0.0273 AC: 3316

Asia WGS AF: 0.00924 AC: 32 AN: 3478

EpiCase AF: 0.0319

EpiControl AF: 0.0327

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:2

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

GFRA1-related disorder Benign:1

May 31, 2024

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0087	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.9	M
PhyloP100		7.2
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.8	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.011	D
Polyphen		0.55	P
Vest4		0.27
MPC		1.3
ClinPred		0.044	T
GERP RS		4.0
Varity_R		0.78
gMVP		0.77
Mutation Taster		=91/9	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: rs8192662; hg19: chr10-118030415;