NM_001480.4:c.16G>T

Variant names:

• chr18-77250564-G-T
• rs929449672
• NM_001480.4:c.16G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001480.4(GALR1):​c.16G>T​(p.Gly6Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000217 in 1,382,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G6R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: GALR1 NM_001480.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.659
• Publications: 0 publications found

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]

ENSG00000309801 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12806994).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALR1	NM_001480.4	c.16G>T	p.Gly6Trp	missense_variant	Exon 1 of 3	ENST00000299727.5	NP_001471.2
GALR1	XM_017025691.2	c.16G>T	p.Gly6Trp	missense_variant	Exon 1 of 3		XP_016881180.1
LOC124904329	XR_007066422.1	n.604+284C>A		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALR1	ENST00000299727.5	c.16G>T	p.Gly6Trp	missense_variant	Exon 1 of 3	1	NM_001480.4	ENSP00000299727.3
ENSG00000309801	ENST00000844037.1	n.162+284C>A		intron_variant	Intron 1 of 1
ENSG00000309801	ENST00000844038.1	n.118+237C>A		intron_variant	Intron 1 of 1
ENSG00000309801	ENST00000844041.1	n.159+284C>A		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000217 AC: 3 AN: 1382054 Hom.: 0 Cov.: 36 AF XY: 0.00000147 AC XY: 1 AN XY: 681820

⚠️ 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: 31510

American (AMR) AF: 0.00 AC: 0 AN: 35672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24866

East Asian (EAS) AF: 0.00 AC: 0 AN: 35746

South Asian (SAS) AF: 0.00 AC: 0 AN: 78962

European-Finnish (FIN) AF: 0.0000285 AC: 1 AN: 35130

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4860

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1077602

Other (OTH) AF: 0.00 AC: 0 AN: 57706

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.022510), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.16G>T (p.G6W) alteration is located in exon 1 (coding exon 1) of the GALR1 gene. This alteration results from a G to T substitution at nucleotide position 16, causing the glycine (G) at amino acid position 6 to be replaced by a tryptophan (W). 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	Uncertain	0.35
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.056	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.51	T
M_CAP	Uncertain	0.089	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.66
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.089
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.012	D
Polyphen		0.0040	B
Vest4		0.23
MutPred		0.41		Loss of disorder (P = 0.0026);
MVP		0.72
MPC		0.49
ClinPred		0.23	T
GERP RS		1.4
Varity_R		0.072
gMVP		0.61
Mutation Taster		=82/18	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: rs929449672; hg19: chr18-74962520;