16-87834579-G-C

Position:

• chr16-87834579-G-C

Variant summary

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

The ENST00000261622.5(SLC7A5):​c.1303C>G​(p.Leu435Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000695 in 1,438,638 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000070 (0 hom.)
• Consequence: SLC7A5 ENST00000261622.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.85

Genes affected

SLC7A5 (HGNC:11063): (solute carrier family 7 member 5) Enables L-leucine transmembrane transporter activity; L-tryptophan transmembrane transporter activity; and thyroid hormone transmembrane transporter activity. Involved in carboxylic acid transport; thyroid hormone transport; and xenobiotic transport. Located in cytosol; intracellular membrane-bounded organelle; and plasma membrane. Is integral component of membrane. Part of amino acid transport complex; apical plasma membrane; and microvillus membrane. [provided by Alliance of Genome Resources, Apr 2022]

MIR6775 (HGNC:50100): (microRNA 6775) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC7A5	NM_003486.7	c.1303C>G	p.Leu435Val	missense_variant	9/10	ENST00000261622.5	NP_003477.4
MIR6775	NR_106833.1			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC7A5	ENST00000261622.5	c.1303C>G	p.Leu435Val	missense_variant	9/10	1	NM_003486.7	ENSP00000261622	P1
SLC7A5	ENST00000565644.5	c.505C>G	p.Leu169Val	missense_variant	9/10	1		ENSP00000454323
SLC7A5	ENST00000563489.1	n.321C>G		non_coding_transcript_exon_variant	2/3	2
MIR6775	ENST00000617557.1			downstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000960 AC: 2 AN: 208424 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 111630

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000214

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000695 AC: 10 AN: 1438638 Hom.: 0 Cov.: 32 AF XY: 0.00000280 AC XY: 2 AN XY: 713086

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000816

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 30, 2022

The c.1303C>G (p.L435V) alteration is located in exon 9 (coding exon 9) of the SLC7A5 gene. This alteration results from a C to G substitution at nucleotide position 1303, causing the leucine (L) at amino acid position 435 to be replaced by a valine (V). 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	0.17
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.025	T;D
Eigen	Benign	0.12
Eigen_PC	Benign	0.092
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D;T
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.57	D;D
MetaSVM	Uncertain	-0.096	T
MutationAssessor	Benign	0.45	.;N
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.2	N;N
REVEL	Pathogenic	0.72
Sift	Benign	0.18	T;T
Sift4G	Benign	0.23	T;T
Polyphen		0.99	.;D
Vest4		0.52
MVP		0.94
MPC		1.4
ClinPred		0.37	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.79

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: rs1038464020; hg19: chr16-87868185;