5-150199346-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_014228.5(SLC6A7):​c.703G>A​(p.Gly235Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,676 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: 𝑓 0.000039 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

SLC6A7
NM_014228.5 missense

Scores

12
6
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 10.0
Variant links:
Genes affected
SLC6A7 (HGNC:11054): (solute carrier family 6 member 7) This gene is a member of the gamma-aminobutyric acid (GABA) neurotransmitter gene family and encodes a high-affinity mammalian brain L-proline transporter protein. This transporter protein differs from other sodium-dependent plasma membrane carriers by its pharmacological specificity, kinetic properties, and ionic requirements. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.981

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SLC6A7NM_014228.5 linkuse as main transcriptc.703G>A p.Gly235Ser missense_variant 5/14 ENST00000230671.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SLC6A7ENST00000230671.7 linkuse as main transcriptc.703G>A p.Gly235Ser missense_variant 5/141 NM_014228.5 P1
SLC6A7ENST00000524041.1 linkuse as main transcriptc.703G>A p.Gly235Ser missense_variant 5/165

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152212
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000327
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000160
AC:
4
AN:
250692
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
135496
show subpopulations
Gnomad AFR exome
AF:
0.0000616
Gnomad AMR exome
AF:
0.00
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:
0.0000176
Gnomad OTH exome
AF:
0.000164
GnomAD4 exome
AF:
0.00000958
AC:
14
AN:
1461464
Hom.:
0
Cov.:
31
AF XY:
0.00000550
AC XY:
4
AN XY:
727020
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.000134
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:
0.00000270
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152212
Hom.:
0
Cov.:
31
AF XY:
0.0000269
AC XY:
2
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000327
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.000121
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.00
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 10, 2022The c.703G>A (p.G235S) alteration is located in exon 5 (coding exon 5) of the SLC6A7 gene. This alteration results from a G to A substitution at nucleotide position 703, causing the glycine (G) at amino acid position 235 to be replaced by a serine (S). 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
Pathogenic
0.97
BayesDel_addAF
Pathogenic
0.32
D
BayesDel_noAF
Pathogenic
0.41
CADD
Pathogenic
31
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.65
D;T
Eigen
Pathogenic
0.94
Eigen_PC
Pathogenic
0.89
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;D
M_CAP
Uncertain
0.18
D
MetaRNN
Pathogenic
0.98
D;D
MetaSVM
Uncertain
0.79
D
MutationAssessor
Pathogenic
3.0
M;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.87
D
PROVEAN
Pathogenic
-5.9
D;D
REVEL
Pathogenic
0.91
Sift
Pathogenic
0.0
D;D
Sift4G
Uncertain
0.023
D;D
Polyphen
1.0
D;.
Vest4
0.92
MutPred
0.96
Gain of disorder (P = 0.1282);Gain of disorder (P = 0.1282);
MVP
0.98
MPC
0.74
ClinPred
0.99
D
GERP RS
5.2
Varity_R
0.96
gMVP
0.91

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs762034555; hg19: chr5-149578909; API