Genetic Variant GALR1:p.Pro18Thr (chr18-77250600-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001480.4(GALR1):c.52C>A(p.Pro18Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000129 in 1,555,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. P18S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

GALR1
NM_001480.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.106

Publications

1 publications found

Variant links:

Genes affected

GALR1 (HGNC:4132): (galanin receptor 1) The neuropeptide galanin elicits a range of biological effects by interaction with specific G-protein-coupled receptors. Galanin receptors are seven-transmembrane proteins shown to activate a variety of intracellular second-messenger pathways. GALR1 inhibits adenylyl cyclase via a G protein of the Gi/Go family. GALR1 is widely expressed in the brain and spinal cord, as well as in peripheral sites such as the small intestine and heart. [provided by RefSeq, Jul 2008]

GALR1 links:

ENSG00000309801 (HGNC:):

ENSG00000309801 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.047357976).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALR1	NM_001480.4 link	c.52C>A	p.Pro18Thr	missense_variant	Exon 1 of 3	ENST00000299727.5	NP_001471.2	P47211
GALR1	XM_017025691.2 link	c.52C>A	p.Pro18Thr	missense_variant	Exon 1 of 3		XP_016881180.1
LOC124904329	XR_007066422.1 link	n.604+248G>T		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GALR1	ENST00000299727.5 link	c.52C>A	p.Pro18Thr	missense_variant	Exon 1 of 3	1	NM_001480.4	ENSP00000299727.3	P47211
ENSG00000309801	ENST00000844037.1 link	n.162+248G>T		intron_variant	Intron 1 of 1
ENSG00000309801	ENST00000844038.1 link	n.118+201G>T		intron_variant	Intron 1 of 1
ENSG00000309801	ENST00000844041.1 link	n.159+248G>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000125

AC:

AN:

159460

AF XY:

0.0000115

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000380

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000843

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.12e-7

AC:

AN:

1403548

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

694384

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32010

American (AMR)

AF:

0.0000267

AC:

AN:

37414

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25256

East Asian (EAS)

AF:

0.00

AC:

AN:

36474

South Asian (SAS)

AF:

0.00

AC:

AN:

80914

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5482

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1086964

Other (OTH)

AF:

0.00

AC:

AN:

58408

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41444

American (AMR)

AF:

0.0000654

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.61

CADD

Benign

0.11

(source)

DANN

Benign

0.56

DEOGEN2

Benign

0.048

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.35

M_CAP

Benign

0.0091

MetaRNN

Benign

0.047

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.3

PhyloP100

-0.11

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.15

REVEL

Benign

0.022

Sift

Benign

0.59

Sift4G

Benign

0.76

Polyphen

0.012

Vest4

0.16

MutPred

0.34

Gain of phosphorylation at P18 (P = 0.0148);

MVP

0.23

MPC

0.47

ClinPred

0.023

GERP RS

-0.099

Varity_R

0.040

gMVP

0.28

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

Publications

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chr18-77250600-C-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

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