dbSNP rs368317123: SLC7A7:p.Val84Phe (chr14-22813149-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_003982.4(SLC7A7):c.250G>T(p.Val84Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V84I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SLC7A7
NM_003982.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.82

Publications

0 publications found

Variant links:

Genes affected

SLC7A7 (HGNC:11065): (solute carrier family 7 member 7) The protein encoded by this gene is the light subunit of a cationic amino acid transporter. This sodium-independent transporter is formed when the light subunit encoded by this gene dimerizes with the heavy subunit transporter protein SLC3A2. This transporter is found in epithelial cell membranes where it transfers cationic and large neutral amino acids from the cell to the extracellular space. Defects in this gene are a cause of lysinuric protein intolerance (LPI). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2011]

SLC7A7 Gene-Disease associations (from GenCC):

lysinuric protein intolerance
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics

SLC7A7 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.826

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SLC7A7	NM_003982.4 link	c.250G>T	p.Val84Phe	missense_variant	Exon 2 of 10	ENST00000674313.1	NP_003973.3
SLC7A7	NM_001126105.3 link	c.250G>T	p.Val84Phe	missense_variant	Exon 3 of 11		NP_001119577.1
SLC7A7	NM_001126106.4 link	c.250G>T	p.Val84Phe	missense_variant	Exon 3 of 11		NP_001119578.1
SLC7A7	XM_011537299.2 link	c.250G>T	p.Val84Phe	missense_variant	Exon 2 of 10		XP_011535601.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC7A7	ENST00000674313.1 link	c.250G>T	p.Val84Phe	missense_variant	Exon 2 of 10		NM_003982.4	ENSP00000501493.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112012

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.76

D;D;D;D;D;D;.;D;.;D;D

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.95

.;.;.;.;D;D;D;D;D;D;D

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.83

D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.60

MutationAssessor

Uncertain

2.1

M;M;M;M;M;.;.;.;.;.;.

PhyloP100

2.8

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-2.3

N;N;N;N;N;D;D;D;D;D;D

REVEL

Pathogenic

0.65

Sift

Uncertain

0.0070

D;D;D;D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.017

D;D;D;D;D;.;.;.;.;.;.

Polyphen

0.99

D;D;D;D;D;.;.;.;.;.;.

Vest4

0.71

MutPred

0.62

Loss of stability (P = 0.158);Loss of stability (P = 0.158);Loss of stability (P = 0.158);Loss of stability (P = 0.158);Loss of stability (P = 0.158);Loss of stability (P = 0.158);Loss of stability (P = 0.158);Loss of stability (P = 0.158);Loss of stability (P = 0.158);Loss of stability (P = 0.158);Loss of stability (P = 0.158);

MVP

0.71

MPC

0.83

ClinPred

0.94

GERP RS

5.4

Varity_R

0.36

gMVP

0.92

Mutation Taster

=51/49

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over