Genetic Variant GALR3:p.Ala225Glu (chr22-37825037-C-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_003614.2(GALR3):c.674C>A(p.Ala225Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00101 in 1,152,814 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00056 ( 1 hom., cov: 34)

Exomes 𝑓: 0.0011 ( 2 hom. )

Consequence

GALR3
NM_003614.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.32

Variant links:

Genes affected

GALR3 (HGNC:4134): (galanin receptor 3) The neuropeptide galanin modulates a variety of physiologic processes including cognition/memory, sensory/pain processing, hormone secretion, and feeding behavior. The human galanin receptors are G protein-coupled receptors that functionally couple to their intracellular effector through distinct signaling pathways. GALR3 is found in many tissues and may be expressed as 1.4-, 2.4-, and 5-kb transcripts [provided by RefSeq, Jul 2008]

GALR3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.26306155).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALR3	NM_003614.2 link	c.674C>A	p.Ala225Glu	missense_variant	Exon 2 of 2	ENST00000249041.3	NP_003605.1	O60755

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALR3	ENST00000249041.3 link	c.674C>A	p.Ala225Glu	missense_variant	Exon 2 of 2	1	NM_003614.2	ENSP00000249041.2		O60755

Frequencies

GnomAD3 genomes

AF:

0.000561

AC:

AN:

148058

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000341

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000336

Gnomad ASJ

AF:

0.000588

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000933

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00107

AC:

1077

AN:

1004756

Hom.:

Cov.:

AF XY:

0.00108

AC XY:

510

AN XY:

473504

show subpopulations

Gnomad4 AFR exome

AF:

0.000201

Gnomad4 AMR exome

AF:

0.000167

Gnomad4 ASJ exome

AF:

0.000559

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00118

Gnomad4 OTH exome

AF:

0.000975

GnomAD4 genome

AF:

0.000561

AC:

AN:

148058

Hom.:

Cov.:

AF XY:

0.000486

AC XY:

AN XY:

72064

show subpopulations

Gnomad4 AFR

AF:

0.000341

Gnomad4 AMR

AF:

0.000336

Gnomad4 ASJ

AF:

0.000588

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000933

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000902

Hom.:

Bravo

AF:

0.000657

ExAC

AF:

0.000160

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.674C>A (p.A225E) alteration is located in exon 2 (coding exon 2) of the GALR3 gene. This alteration results from a C to A substitution at nucleotide position 674, causing the alanine (A) at amino acid position 225 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.031

Eigen

Benign

-0.020

Eigen_PC

Benign

-0.0061

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.35

M_CAP

Uncertain

0.29

MetaRNN

Benign

0.26

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.97

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

0.31

REVEL

Benign

0.28

Sift

Benign

0.055

Sift4G

Benign

0.13

Polyphen

1.0

Vest4

0.43

MVP

0.59

MPC

2.1

ClinPred

0.98

GERP RS

3.6

Varity_R

0.27

gMVP

0.27

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over