Genetic Variant NM_014228.5:c.587G>A (chr5-150199230-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014228.5(SLC6A7):c.587G>A(p.Arg196His) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000125 in 1,445,726 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

SLC6A7
NM_014228.5 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.24

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]

SLC6A7 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC6A7	NM_014228.5 link	c.587G>A	p.Arg196His	missense_variant, splice_region_variant	Exon 5 of 14	ENST00000230671.7	NP_055043.2	Q99884

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC6A7	ENST00000230671.7 link	c.587G>A	p.Arg196His	missense_variant, splice_region_variant	Exon 5 of 14	1	NM_014228.5	ENSP00000230671.2		Q99884
SLC6A7	ENST00000524041.1 link	c.587G>A	p.Arg196His	missense_variant, splice_region_variant	Exon 5 of 16	5		ENSP00000428200.1		E5RJL1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000289

AC:

AN:

241938

Hom.:

AF XY:

0.0000306

AC XY:

AN XY:

130650

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000346

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000456

Gnomad OTH exome

AF:

0.000171

GnomAD4 exome

AF:

0.0000125

AC:

AN:

1445726

Hom.:

Cov.:

AF XY:

0.0000125

AC XY:

AN XY:

717244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000254

Gnomad4 SAS exome

AF:

0.0000949

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000817

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.587G>A (p.R196H) 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 587, causing the arginine (R) at amino acid position 196 to be replaced by a histidine (H). 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

0.18

BayesDel_addAF

Benign

-0.053

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

T;T

Eigen

Benign

0.11

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.95

D;D

M_CAP

Benign

0.041

MetaRNN

Uncertain

0.66

D;D

MetaSVM

Benign

-0.56

MutationAssessor

Benign

1.9

L;.

PrimateAI

Uncertain

0.61

PROVEAN

Benign

1.2

N;N

REVEL

Uncertain

0.37

Sift

Benign

0.50

T;T

Sift4G

Benign

0.59

T;T

Polyphen

0.61

P;.

Vest4

0.70

MVP

0.89

MPC

0.83

ClinPred

0.57

GERP RS

5.4

Varity_R

0.15

gMVP

0.65

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over