14-22773635-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003982.4(SLC7A7):c.1511A>T(p.Lys504Met) 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 1,461,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SLC7A7 NM_003982.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.50

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20645836).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC7A7	NM_003982.4	c.1511A>T	p.Lys504Met	missense_variant	10/10	ENST00000674313.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC7A7	ENST00000674313.1	c.1511A>T	p.Lys504Met	missense_variant	10/10		NM_003982.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251480 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 6.84e-7 AC: 1 AN: 1461850 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 28, 2022

The c.1511A>T (p.K504M) alteration is located in exon 11 (coding exon 9) of the SLC7A7 gene. This alteration results from a A to T substitution at nucleotide position 1511, causing the lysine (K) at amino acid position 504 to be replaced by a methionine (M). 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	0.14
BayesDel_addAF	Uncertain	0.065	T
BayesDel_noAF	Uncertain	-0.060
Cadd	Benign	19
Dann	Uncertain	0.98
DEOGEN2	Benign	0.17	T;T;T;T;T;T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.058
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.21	T;T;T;T;T;T
MetaSVM	Uncertain	0.047	D
MutationAssessor	Benign	1.7	L;L;L;L;L;.
MutationTaster	Benign	0.99	D;D;D;D;D;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.1	N;N;N;N;N;N
REVEL	Uncertain	0.43
Sift	Benign	0.045	D;D;D;D;D;D
Sift4G	Uncertain	0.033	D;D;D;D;D;D
Polyphen		0.020	B;B;B;B;B;.
Vest4		0.43
MutPred		0.17		Loss of ubiquitination at K504 (P = 0.0019);Loss of ubiquitination at K504 (P = 0.0019);Loss of ubiquitination at K504 (P = 0.0019);Loss of ubiquitination at K504 (P = 0.0019);Loss of ubiquitination at K504 (P = 0.0019);.;
MVP		0.49
MPC		0.26
ClinPred		0.36	T
GERP RS		5.5
Varity_R		0.092
gMVP		0.60

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

Other links and lift over

dbSNP: rs1221063158; hg19: chr14-23242844;