10-116089842-T-G

Variant names:

• chr10-116089842-T-G
• rs2072276
• NM_005264.8:c.1096A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005264.8(GFRA1):​c.1096A>C​(p.Thr366Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,362 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T366A) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GFRA1 NM_005264.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.73
• Publications: 0 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30009228).

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.1096A>C	p.Thr366Pro	missense	Exon 9 of 11	NP_005255.1	P56159-1
	GFRA1	NM_001348098.4		c.1096A>C	p.Thr366Pro	missense	Exon 9 of 11	NP_001335027.1	P56159-1
	GFRA1	NM_001145453.4		c.1081A>C	p.Thr361Pro	missense	Exon 8 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.1096A>C	p.Thr366Pro	missense	Exon 9 of 11	ENSP00000347591.6	P56159-1
	GFRA1	ENST00000369236.5	TSL:1	c.1081A>C	p.Thr361Pro	missense	Exon 7 of 9	ENSP00000358239.1	P56159-2
	GFRA1	ENST00000369234.5	TSL:5	c.1096A>C	p.Thr366Pro	missense	Exon 9 of 11	ENSP00000358237.4	P56159-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461362 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727010

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111548

Other (OTH) AF: 0.00 AC: 0 AN: 60380

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.080	T
Eigen	Benign	-0.17
Eigen_PC	Benign	0.029
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.7	L
PhyloP100		3.7
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.81	N
REVEL	Benign	0.059
Sift	Benign	0.45	T
Sift4G	Benign	0.40	T
Polyphen		0.0040	B
Vest4		0.41
MutPred		0.27		Gain of relative solvent accessibility (P = 0.0479)
MVP		0.65
MPC		0.53
ClinPred		0.49	T
GERP RS		5.0
Varity_R		0.14
gMVP		0.45
Mutation Taster		=88/12	polymorphism

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: rs2072276; hg19: chr10-117849353;