Genetic Variant GAL:p.Arg88Leu (chr11-68688888-G-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_015973.5(GAL):c.263G>T(p.Arg88Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 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. R88H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GAL
NM_015973.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.46

Publications

0 publications found

Variant links:

Genes affected

GAL (HGNC:4114): (galanin and GMAP prepropeptide) This gene encodes a neuroendocrine peptide that is widely expressed in the central and peripheral nervous systems and also the gastrointestinal tract, pancreas, adrenal gland and urogenital tract. The encoded protein is a precursor that is proteolytically processed to generate two mature peptides: galanin and galanin message-associated peptide (GMAP). Galanin has diverse physiological functions including nociception, feeding and energy homeostasis, osmotic regulation and water balance. GMAP has been demonstrated to possess antifungal activity and hypothesized to be part of the innate immune system. [provided by RefSeq, Jul 2015]

GAL Gene-Disease associations (from GenCC):

familial temporal lobe epilepsy 8
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

GAL links:

LOC107984343 (HGNC:):

LOC107984343 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.944

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015973.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAL	NM_015973.5	MANE Select	c.263G>T	p.Arg88Leu	missense	Exon 5 of 6	NP_057057.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GAL	ENST00000265643.4	TSL:1 MANE Select	c.263G>T	p.Arg88Leu	missense	Exon 5 of 6	ENSP00000265643.3	P22466
GAL	ENST00000933457.1		c.461G>T	p.Arg154Leu	missense	Exon 6 of 7	ENSP00000603516.1
GAL	ENST00000933456.1		c.317G>T	p.Arg106Leu	missense	Exon 5 of 6	ENSP00000603515.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1418160

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

708442

African (AFR)

AF:

0.00

AC:

AN:

32666

American (AMR)

AF:

0.00

AC:

AN:

44646

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25836

East Asian (EAS)

AF:

0.00

AC:

AN:

39506

South Asian (SAS)

AF:

0.00

AC:

AN:

85294

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5688

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1072268

Other (OTH)

AF:

0.00

AC:

AN:

58860

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial temporal lobe epilepsy 8 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Uncertain

0.044

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.69

Eigen

Benign

0.0080

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.76

M_CAP

Benign

0.021

MetaRNN

Pathogenic

0.94

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.9

PhyloP100

1.5

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-4.0

REVEL

Benign

0.24

Sift

Benign

0.17

Sift4G

Benign

0.19

Polyphen

0.90

Vest4

0.75

MutPred

0.73

Loss of disorder (P = 0.0662)

MVP

0.69

MPC

0.44

ClinPred

0.98

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.20

gMVP

0.52

Mutation Taster

=73/27

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over