rs17281188

Variant names:

• chrX-48459000-A-G
• rs17281188
• NM_033518.4:c.1352T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_033518.4(SLC38A5):​c.1352T>C​(p.Met451Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0768 in 1,194,220 control chromosomes in the GnomAD database, including 2,564 homozygotes. There are 30,323 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.076 (277 hom., 2645 hem., cov: 23)
  • Exomes 𝑓: 0.077 (2287 hom. 27678 hem.)
• Consequence: SLC38A5 NM_033518.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 8.31
• Publications: 15 publications found

Genes affected

SLC38A5 (HGNC:18070): (solute carrier family 38 member 5) The protein encoded by this gene is a system N sodium-coupled amino acid transporter. The encoded protein transports glutamine, asparagine, histidine, serine, alanine, and glycine across the cell membrane, but does not transport charged amino acids, imino acids, or N-alkylated amino acids. Alternative splicing results in multiple transcript variants, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Aug 2013]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017329752).
• BP6: Variant X-48459000-A-G is Benign according to our data. Variant chrX-48459000-A-G is described in ClinVar as Benign. ClinVar VariationId is 403457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC38A5	NM_033518.4	c.1352T>C	p.Met451Thr	missense_variant	Exon 17 of 17	ENST00000620913.5	NP_277053.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC38A5	ENST00000620913.5	c.1352T>C	p.Met451Thr	missense_variant	Exon 17 of 17	5	NM_033518.4	ENSP00000481291.1

Frequencies

GnomAD3 genomes AF: 0.0760 AC: 8572 AN: 112828 Hom.: 277 Cov.: 23

Gnomad AFR AF: 0.0401

Gnomad AMI AF: 0.168

Gnomad AMR AF: 0.163

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.0887

Gnomad SAS AF: 0.109

Gnomad FIN AF: 0.0693

Gnomad MID AF: 0.0462

Gnomad NFE AF: 0.0736

Gnomad OTH AF: 0.0994

GnomAD2 exomes AF: 0.0846 AC: 12809 AN: 151431 AF XY: 0.0853

Gnomad AFR exome AF: 0.0324

Gnomad AMR exome AF: 0.133

Gnomad ASJ exome AF: 0.121

Gnomad EAS exome AF: 0.0785

Gnomad FIN exome AF: 0.0631

Gnomad NFE exome AF: 0.0714

Gnomad OTH exome AF: 0.0999

GnomAD4 exome AF: 0.0769 AC: 83183 AN: 1081340 Hom.: 2287 Cov.: 33 AF XY: 0.0784 AC XY: 27678 AN XY: 352944

African (AFR) AF: 0.0373 AC: 970 AN: 26000

American (AMR) AF: 0.137 AC: 4562 AN: 33183

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 2380 AN: 18975

East Asian (EAS) AF: 0.0892 AC: 2622 AN: 29380

South Asian (SAS) AF: 0.102 AC: 5279 AN: 51864

European-Finnish (FIN) AF: 0.0704 AC: 2764 AN: 39261

Middle Eastern (MID) AF: 0.0955 AC: 393 AN: 4114

European-Non Finnish (NFE) AF: 0.0726 AC: 60466 AN: 833139

Other (OTH) AF: 0.0825 AC: 3747 AN: 45424

GnomAD4 genome AF: 0.0759 AC: 8569 AN: 112880 Hom.: 277 Cov.: 23 AF XY: 0.0755 AC XY: 2645 AN XY: 35048

African (AFR) AF: 0.0401 AC: 1250 AN: 31185

American (AMR) AF: 0.162 AC: 1741 AN: 10731

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 329 AN: 2658

East Asian (EAS) AF: 0.0881 AC: 313 AN: 3552

South Asian (SAS) AF: 0.110 AC: 305 AN: 2780

European-Finnish (FIN) AF: 0.0693 AC: 436 AN: 6290

Middle Eastern (MID) AF: 0.0415 AC: 9 AN: 217

European-Non Finnish (NFE) AF: 0.0736 AC: 3920 AN: 53242

Other (OTH) AF: 0.0982 AC: 152 AN: 1548

Alfa AF: 0.0744 Hom.: 3918

Bravo AF: 0.0827

TwinsUK AF: 0.0734 AC: 272

ALSPAC AF: 0.0807 AC: 233

ESP6500AA AF: 0.0324 AC: 124

ESP6500EA AF: 0.0744 AC: 500

ExAC AF: 0.0716 AC: 8510

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.27	T;T;.;T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	.;T;D;D
MetaRNN	Benign	0.0017	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M;M;.;.
PhyloP100		8.3
PrimateAI	Uncertain	0.62	T
Sift4G	Benign	0.12	T;T;T;D
Polyphen		1.0	D;D;.;.
Vest4		0.25
ClinPred		0.048	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.59
gMVP		0.92
Mutation Taster		=92/8	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17281188; hg19: chrX-48317386; COSMIC: COSV58333255; COSMIC: COSV58333255;