5-150197220-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_014228.5(SLC6A7):​c.528C>A​(p.Asn176Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,608 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 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

SLC6A7
NM_014228.5 missense

Scores

1
7
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.50
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 Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.752

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SLC6A7NM_014228.5 linkc.528C>A p.Asn176Lys missense_variant Exon 4 of 14 ENST00000230671.7 NP_055043.2 Q99884

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SLC6A7ENST00000230671.7 linkc.528C>A p.Asn176Lys missense_variant Exon 4 of 14 1 NM_014228.5 ENSP00000230671.2 Q99884
SLC6A7ENST00000524041.1 linkc.528C>A p.Asn176Lys missense_variant Exon 4 of 16 5 ENSP00000428200.1 E5RJL1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152264
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
249234
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
134928
show subpopulations
Gnomad AFR exome
AF:
0.0000617
Gnomad AMR exome
AF:
0.0000579
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461344
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
726958
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000447
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152264
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74386
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Feb 12, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.528C>A (p.N176K) alteration is located in exon 4 (coding exon 4) of the SLC6A7 gene. This alteration results from a C to A substitution at nucleotide position 528, causing the asparagine (N) at amino acid position 176 to be replaced by a lysine (K). 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
0.10
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.34
CADD
Benign
6.3
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.42
T;T
Eigen
Benign
-0.74
Eigen_PC
Benign
-0.97
FATHMM_MKL
Benign
0.37
N
LIST_S2
Benign
0.72
T;T
M_CAP
Benign
0.082
D
MetaRNN
Pathogenic
0.75
D;D
MetaSVM
Benign
-0.34
T
MutationAssessor
Benign
1.8
L;.
PrimateAI
Uncertain
0.59
T
PROVEAN
Uncertain
-2.8
D;D
REVEL
Uncertain
0.48
Sift
Uncertain
0.022
D;D
Sift4G
Uncertain
0.017
D;D
Polyphen
0.99
D;.
Vest4
0.81
MutPred
0.43
Gain of ubiquitination at N176 (P = 0.0131);Gain of ubiquitination at N176 (P = 0.0131);
MVP
0.66
MPC
0.79
ClinPred
0.96
D
GERP RS
-6.1
Varity_R
0.18
gMVP
0.74

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: rs753309865; hg19: chr5-149576783; API