14-22773338-G-A

Variant names:

• chr14-22773338-G-A
• rs143575981
• NM_003982.4:c.*272C>T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_003982.4(SLC7A7):​c.*272C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0109 in 561,806 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0099 (5 hom., cov: 32)
  • Exomes 𝑓: 0.011 (43 hom.)
• Consequence: SLC7A7 NM_003982.4 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.176

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 14-22773338-G-A is Benign according to our data. Variant chr14-22773338-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 882078.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00994 (1513/152276) while in subpopulation NFE AF= 0.0165 (1122/68018). AF 95% confidence interval is 0.0157. There are 5 homozygotes in gnomad4. There are 638 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC7A7	NM_003982.4	c.*272C>T		3_prime_UTR_variant	Exon 10 of 10	ENST00000674313.1	NP_003973.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC7A7	ENST00000674313	c.*272C>T		3_prime_UTR_variant	Exon 10 of 10		NM_003982.4	ENSP00000501493.1

Frequencies

GnomAD3 genomes AF: 0.00995 AC: 1514 AN: 152158 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00280

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0117

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00320

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0165

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00972 AC: 1283 AN: 132000 Hom.: 9 AF XY: 0.00939 AC XY: 675 AN XY: 71874

Gnomad AFR exome AF: 0.00191

Gnomad AMR exome AF: 0.00896

Gnomad ASJ exome AF: 0.00580

Gnomad EAS exome AF: 0.000185

Gnomad SAS exome AF: 0.00267

Gnomad FIN exome AF: 0.00238

Gnomad NFE exome AF: 0.0173

Gnomad OTH exome AF: 0.0139

GnomAD4 exome AF: 0.0112 AC: 4587 AN: 409530 Hom.: 43 Cov.: 0 AF XY: 0.0106 AC XY: 2400 AN XY: 226530

Gnomad4 AFR exome AF: 0.00323

Gnomad4 AMR exome AF: 0.00920

Gnomad4 ASJ exome AF: 0.00670

Gnomad4 EAS exome AF: 0.0000545

Gnomad4 SAS exome AF: 0.00256

Gnomad4 FIN exome AF: 0.00241

Gnomad4 NFE exome AF: 0.0160

Gnomad4 OTH exome AF: 0.0125

GnomAD4 genome AF: 0.00994 AC: 1513 AN: 152276 Hom.: 5 Cov.: 32 AF XY: 0.00857 AC XY: 638 AN XY: 74452

Gnomad4 AFR AF: 0.00279

Gnomad4 AMR AF: 0.0116

Gnomad4 ASJ AF: 0.00807

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00320

Gnomad4 NFE AF: 0.0165

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.0107 Hom.: 3

Bravo AF: 0.0101

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autoinflammatory syndrome Uncertain:1

Dec 19, 2016

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lysinuric protein intolerance Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:1

Mar 06, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	8.3
DANN	Benign	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

Other links and lift over

dbSNP: rs143575981; hg19: chr14-23242547;