chr14-23128047-G-C

Position:

• chr14-23128047-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012244.4(SLC7A8):​c.1413C>G​(p.His471Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SLC7A8 NM_012244.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.920

Genes affected

SLC7A8 (HGNC:11066): (solute carrier family 7 member 8) Enables several functions, including neutral amino acid transmembrane transporter activity; thyroid hormone transmembrane transporter activity; and toxin transmembrane transporter activity. Involved in L-alanine import across plasma membrane; L-leucine import across plasma membrane; and thyroid hormone transport. Located in plasma membrane. Part of basolateral plasma membrane and microvillus membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16222635).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC7A8	NM_012244.4	c.1413C>G	p.His471Gln	missense_variant	10/11	ENST00000316902.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC7A8	ENST00000316902.12	c.1413C>G	p.His471Gln	missense_variant	10/11	1	NM_012244.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461846 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727236

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: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

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

Jul 12, 2023

The c.1413C>G (p.H471Q) alteration is located in exon 10 (coding exon 10) of the SLC7A8 gene. This alteration results from a C to G substitution at nucleotide position 1413, causing the histidine (H) at amino acid position 471 to be replaced by a glutamine (Q). 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	0.082
BayesDel_addAF	Benign	0.0044	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.23	T;.;.;.
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.69	T;T;T;T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.16	T;T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	0.97	L;.;.;.
MutationTaster	Benign	0.99	D;D;D;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.16	N;N;N;N
REVEL	Benign	0.19
Sift	Benign	0.079	T;T;T;T
Sift4G	Benign	0.17	T;T;T;T
Polyphen		0.0030	B;.;.;.
Vest4		0.17
MutPred		0.56		Loss of sheet (P = 0.007);.;.;.;
MVP		0.72
MPC		0.15
ClinPred		0.18	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.081
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2048595204; hg19: chr14-23597256;