14-22774477-G-C

Variant names:

• chr14-22774477-G-C
• rs771254387
• NM_003982.4:c.1122C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003982.4(SLC7A7):​c.1122C>G​(p.Cys374Trp) 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 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. C374C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SLC7A7 NM_003982.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0820
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003982.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC7A7	NM_003982.4	MANE Select	c.1122C>G	p.Cys374Trp	missense	Exon 8 of 10	NP_003973.3
	SLC7A7	NM_001126105.3		c.1122C>G	p.Cys374Trp	missense	Exon 9 of 11	NP_001119577.1
	SLC7A7	NM_001126106.4		c.1122C>G	p.Cys374Trp	missense	Exon 9 of 11	NP_001119578.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC7A7	ENST00000674313.1	MANE Select	c.1122C>G	p.Cys374Trp	missense	Exon 8 of 10	ENSP00000501493.1
	SLC7A7	ENST00000397528.8	TSL:1	c.1122C>G	p.Cys374Trp	missense	Exon 9 of 11	ENSP00000380662.4
	SLC7A7	ENST00000397529.6	TSL:1	c.1122C>G	p.Cys374Trp	missense	Exon 8 of 10	ENSP00000380663.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.76	D
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.44	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.082
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.051	T
Polyphen		1.0	D
Vest4		0.64
MutPred		0.53		Loss of stability (P = 0.1528)
MVP		0.75
MPC		0.84
ClinPred		0.99	D
GERP RS		-2.4
Varity_R		0.76
gMVP		0.78
Mutation Taster		=24/76	disease causing

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

Other links and lift over

dbSNP: rs771254387; hg19: chr14-23243686;