14-22813127-G-A

Position:

• chr14-22813127-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003982.4(SLC7A7):​c.272C>T​(p.Ala91Val) variant causes a missense change. The variant allele was found at a frequency of 0.016 in 1,614,104 control chromosomes in the GnomAD database, including 261 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (19 hom., cov: 31)
  • Exomes 𝑓: 0.016 (242 hom.)
• Consequence: SLC7A7 NM_003982.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: 6.88

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014431596).
• BP6: Variant 14-22813127-G-A is Benign according to our data. Variant chr14-22813127-G-A is described in ClinVar as [Benign]. Clinvar id is 380186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-22813127-G-A is described in Lovd as [Likely_benign]. Variant chr14-22813127-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0128 (1949/152212) while in subpopulation NFE AF= 0.0211 (1437/68006). AF 95% confidence interval is 0.0202. There are 19 homozygotes in gnomad4. There are 901 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC7A7	NM_003982.4	c.272C>T	p.Ala91Val	missense_variant	2/10	ENST00000674313.1	NP_003973.3
SLC7A7	NM_001126105.3	c.272C>T	p.Ala91Val	missense_variant	3/11		NP_001119577.1
SLC7A7	NM_001126106.4	c.272C>T	p.Ala91Val	missense_variant	3/11		NP_001119578.1
SLC7A7	XM_011537299.2	c.272C>T	p.Ala91Val	missense_variant	2/10		XP_011535601.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC7A7	ENST00000674313.1	c.272C>T	p.Ala91Val	missense_variant	2/10		NM_003982.4	ENSP00000501493.1

Frequencies

GnomAD3 genomes AF: 0.0128 AC: 1950 AN: 152096 Hom.: 19 Cov.: 31

Gnomad AFR AF: 0.00302

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.00734

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0210

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0211

Gnomad OTH AF: 0.00909

GnomAD3 exomes AF: 0.0125 AC: 3138 AN: 251372 Hom.: 28 AF XY: 0.0122 AC XY: 1652 AN XY: 135870

Gnomad AFR exome AF: 0.00277

Gnomad AMR exome AF: 0.00512

Gnomad ASJ exome AF: 0.0101

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.0246

Gnomad NFE exome AF: 0.0193

Gnomad OTH exome AF: 0.0134

GnomAD4 exome AF: 0.0163 AC: 23868 AN: 1461892 Hom.: 242 Cov.: 71 AF XY: 0.0160 AC XY: 11618 AN XY: 727246

Gnomad4 AFR exome AF: 0.00239

Gnomad4 AMR exome AF: 0.00599

Gnomad4 ASJ exome AF: 0.00888

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000614

Gnomad4 FIN exome AF: 0.0247

Gnomad4 NFE exome AF: 0.0189

Gnomad4 OTH exome AF: 0.0147

GnomAD4 genome AF: 0.0128 AC: 1949 AN: 152212 Hom.: 19 Cov.: 31 AF XY: 0.0121 AC XY: 901 AN XY: 74432

Gnomad4 AFR AF: 0.00301

Gnomad4 AMR AF: 0.00727

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0210

Gnomad4 NFE AF: 0.0211

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.0175 Hom.: 74

Bravo AF: 0.0119

TwinsUK AF: 0.0154 AC: 57

ALSPAC AF: 0.0182 AC: 70

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0201 AC: 173

ExAC AF: 0.0123 AC: 1487

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0184

EpiControl AF: 0.0161

ClinVar

Significance: Benign

Submissions summary: Benign:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	SLC7A7: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Lysinuric protein intolerance Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 27, 2019	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 03, 2021	Variant summary: SLC7A7 c.272C>T (p.Ala91Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.012 in 251372 control chromosomes in the gnomAD database, including 28 homozygotes. The observed variant frequency is approximately 11 fold of the estimated maximal expected allele frequency for a pathogenic variant in SLC7A7 causing Lysinuric Protein Intolerance phenotype (0.0011), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.272C>T in individuals affected with Lysinuric Protein Intolerance and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 07, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;D;D;D;D;D;.;D;.;D;D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	.;.;.;.;D;D;D;D;D;D;D
MetaRNN	Benign	0.014	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.54	D
MutationAssessor	Uncertain	2.9	M;M;M;M;M;.;.;.;.;.;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.8	D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0060	D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.020	D;D;D;D;D;.;.;.;.;.;.
Polyphen		0.99	D;D;D;D;D;.;.;.;.;.;.
Vest4		0.15
MPC		0.65
ClinPred		0.011	T
GERP RS		5.4
Varity_R		0.54
gMVP		0.89

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: rs11568438; hg19: chr14-23282336; COSMIC: COSV53539800; COSMIC: COSV53539800;