16-87834442-G-C

Variant names:

• chr16-87834442-G-C
• rs532078127
• NM_003486.7:c.1440C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003486.7(SLC7A5):​c.1440C>G​(p.Asn480Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000213 in 1,405,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SLC7A5 NM_003486.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.10

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37536758).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC7A5	NM_003486.7	c.1440C>G	p.Asn480Lys	missense_variant	Exon 9 of 10	ENST00000261622.5	NP_003477.4
MIR6775	NR_106833.1	n.*150C>G		downstream_gene_variant
MIR6775	unassigned_transcript_2906	n.*150C>G		downstream_gene_variant
MIR6775	unassigned_transcript_2907	n.*189C>G		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC7A5	ENST00000261622.5	c.1440C>G	p.Asn480Lys	missense_variant	Exon 9 of 10	1	NM_003486.7	ENSP00000261622.4
SLC7A5	ENST00000565644.5	c.642C>G	p.Asn214Lys	missense_variant	Exon 9 of 10	1		ENSP00000454323.1
SLC7A5	ENST00000563489.1	n.458C>G		non_coding_transcript_exon_variant	Exon 2 of 3	2
MIR6775	ENST00000617557.1	n.*150C>G		downstream_gene_variant		6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000121 AC: 2 AN: 165352 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 87328

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000796

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: 0.00000213 AC: 3 AN: 1405950 Hom.: 0 Cov.: 32 AF XY: 0.00000144 AC XY: 1 AN XY: 693998

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000833

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.: 33

Bravo AF: 0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1440C>G (p.N480K) 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 1440, causing the asparagine (N) at amino acid position 480 to be replaced by a lysine (K). 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	0.13
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.025	T;T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.018
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.38	T;T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	1.9	.;L
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.24
Sift	Benign	1.0	T;T
Sift4G	Benign	0.79	T;T
Polyphen		0.0	.;B
Vest4		0.59
MutPred		0.60		.;Gain of methylation at N480 (P = 0.0121);
MVP		0.82
MPC		0.84
ClinPred		0.21	T
GERP RS		4.5
Varity_R		0.14
gMVP		0.84

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: rs532078127; hg19: chr16-87868048;