chr22-37824767-C-T

Variant names:

• chr22-37824767-C-T
• rs1432567350
• NM_003614.2:c.404C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003614.2(GALR3):​c.404C>T​(p.Thr135Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000178 in 1,123,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: GALR3 NM_003614.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.31

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.903

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALR3	NM_003614.2	c.404C>T	p.Thr135Met	missense_variant	Exon 2 of 2	ENST00000249041.3	NP_003605.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALR3	ENST00000249041.3	c.404C>T	p.Thr135Met	missense_variant	Exon 2 of 2	1	NM_003614.2	ENSP00000249041.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000178 AC: 2 AN: 1123854 Hom.: 0 Cov.: 30 AF XY: 0.00000184 AC XY: 1 AN XY: 543490

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000212

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.404C>T (p.T135M) alteration is located in exon 2 (coding exon 2) of the GALR3 gene. This alteration results from a C to T substitution at nucleotide position 404, causing the threonine (T) at amino acid position 135 to be replaced by a methionine (M). 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	0.56
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	-0.038	T
MutationAssessor	Pathogenic	3.4	M
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.71
MutPred		0.58		Loss of phosphorylation at T135 (P = 0.0248);
MVP		0.80
MPC		2.0
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.80
gMVP		0.60

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: rs1432567350; hg19: chr22-38220774;