chr18-77250570-C-T

Variant names:

• chr18-77250570-C-T
• rs201461949
• NM_001480.4:c.22C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001480.4(GALR1):​c.22C>T​(p.Leu8Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000147 in 1,537,074 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00080 (1 hom., cov: 34)
  • Exomes 𝑓: 0.000075 (0 hom.)
• Consequence: GALR1 NM_001480.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0630
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0052224398).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALR1	NM_001480.4	c.22C>T	p.Leu8Phe	missense_variant	Exon 1 of 3	ENST00000299727.5	NP_001471.2
GALR1	XM_017025691.2	c.22C>T	p.Leu8Phe	missense_variant	Exon 1 of 3		XP_016881180.1
LOC124904329	XR_007066422.1	n.604+278G>A		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALR1	ENST00000299727.5	c.22C>T	p.Leu8Phe	missense_variant	Exon 1 of 3	1	NM_001480.4	ENSP00000299727.3
ENSG00000309801	ENST00000844037.1	n.162+278G>A		intron_variant	Intron 1 of 1
ENSG00000309801	ENST00000844038.1	n.118+231G>A		intron_variant	Intron 1 of 1
ENSG00000309801	ENST00000844041.1	n.159+278G>A		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.000775 AC: 118 AN: 152166 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00273

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000131 AC: 18 AN: 136984 AF XY: 0.0000670

Gnomad AFR exome AF: 0.00193

Gnomad AMR exome AF: 0.000121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000928

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000242

GnomAD4 exome AF: 0.0000751 AC: 104 AN: 1384794 Hom.: 0 Cov.: 37 AF XY: 0.0000717 AC XY: 49 AN XY: 683464

African (AFR) AF: 0.00225 AC: 71 AN: 31584

American (AMR) AF: 0.000140 AC: 5 AN: 35808

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25020

East Asian (EAS) AF: 0.0000279 AC: 1 AN: 35800

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79276

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35686

Middle Eastern (MID) AF: 0.000198 AC: 1 AN: 5052

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078782

Other (OTH) AF: 0.000433 AC: 25 AN: 57786

GnomAD4 genome AF: 0.000801 AC: 122 AN: 152280 Hom.: 1 Cov.: 34 AF XY: 0.000819 AC XY: 61 AN XY: 74452

African (AFR) AF: 0.00279 AC: 116 AN: 41578

American (AMR) AF: 0.000131 AC: 2 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5134

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68010

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000330 Hom.: 0

Bravo AF: 0.000876

ExAC AF: 0.000116 AC: 12

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 01, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.22C>T (p.L8F) 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 22, causing the leucine (L) at amino acid position 8 to be replaced by a phenylalanine (F). 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	0.11
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.050	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.063
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.12
Sift	Benign	0.65	T
Sift4G	Benign	0.74	T
Polyphen		0.0	B
Vest4		0.050
MVP		0.54
MPC		0.45
ClinPred		0.0034	T
GERP RS		0.14
Varity_R		0.043
gMVP		0.30
Mutation Taster		=95/5	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: rs201461949; hg19: chr18-74962526;