18-77250600-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001480.4(GALR1):c.52C>T(p.Pro18Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000816 in 1,555,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: GALR1 NM_001480.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.106

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]

LOC124904329 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.004375577).
• BP6: Variant 18-77250600-C-T is Benign according to our data. Variant chr18-77250600-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2568908.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GALR1	NM_001480.4	c.52C>T	p.Pro18Ser	missense_variant	1/3	ENST00000299727.5
LOC124904329	XR_007066422.1	n.604+248G>A		intron_variant, non_coding_transcript_variant
GALR1	XM_017025691.2	c.52C>T	p.Pro18Ser	missense_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALR1	ENST00000299727.5	c.52C>T	p.Pro18Ser	missense_variant	1/3	1	NM_001480.4	P1

Frequencies

GnomAD3 genomes AF: 0.000486 AC: 74 AN: 152158 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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

GnomAD3 exomes AF: 0.000119 AC: 19 AN: 159460 Hom.: 0 AF XY: 0.0000802 AC XY: 7 AN XY: 87290

Gnomad AFR exome AF: 0.00189

Gnomad AMR exome AF: 0.000114

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000152

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000378 AC: 53 AN: 1403548 Hom.: 0 Cov.: 36 AF XY: 0.0000317 AC XY: 22 AN XY: 694384

Gnomad4 AFR exome AF: 0.00122

Gnomad4 AMR exome AF: 0.000160

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000184

Gnomad4 OTH exome AF: 0.000103

GnomAD4 genome AF: 0.000486 AC: 74 AN: 152274 Hom.: 0 Cov.: 34 AF XY: 0.000484 AC XY: 36 AN XY: 74454

Gnomad4 AFR AF: 0.00171

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000612

ExAC AF: 0.0000861 AC: 10

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 20, 2023

The c.52C>T (p.P18S) alteration is located in exon 1 (coding exon 1) of the GALR1 gene. This alteration results from a C to T substitution at nucleotide position 52, causing the proline (P) at amino acid position 18 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

GALR1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 08, 2022

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	0.088
Dann	Benign	0.77
DEOGEN2	Benign	0.045	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.51	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.16	N
REVEL	Benign	0.025
Sift	Benign	0.74	T
Sift4G	Benign	0.95	T
Polyphen		0.0	B
Vest4		0.086
MutPred		0.38		Loss of catalytic residue at P18 (P = 1e-04);
MVP		0.21
MPC		0.42
ClinPred		0.0072	T
GERP RS		-0.099
Varity_R		0.029
gMVP		0.29

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

Other links and lift over

dbSNP: rs539654659; hg19: chr18-74962556;