X-70925907-C-G

Variant names:

• chrX-70925907-C-G
• rs149447856
• NM_032803.6:c.1766G>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_032803.6(SLC7A3):​c.1766G>C​(p.Ser589Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00272 in 1,209,657 control chromosomes in the GnomAD database, including 7 homozygotes. There are 1,109 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., 80 hem., cov: 23)
  • Exomes 𝑓: 0.0028 (6 hom. 1029 hem.)
• Consequence: SLC7A3 NM_032803.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 7.40
• Publications: 15 publications found

Genes affected

SLC7A3 (HGNC:11061): (solute carrier family 7 member 3) This gene encodes a member of the solute carrier family 7. The encoded protein is a sodium-independent cationic amino acid transporter. Alternate splicing results in multiple transcripts that encoded the same protein.[provided by RefSeq, May 2010]

SLC7A3 Gene-Disease associations (from GenCC):

• autism spectrum disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.021085083).
• BP6: Variant X-70925907-C-G is Benign according to our data. Variant chrX-70925907-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 807745.
• BS2: High AC in GnomAd4 at 264 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032803.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC7A3	NM_032803.6	MANE Select	c.1766G>C	p.Ser589Thr	missense	Exon 12 of 12	NP_116192.4
	SLC7A3	NM_001048164.3		c.1766G>C	p.Ser589Thr	missense	Exon 12 of 12	NP_001041629.1	Q8WY07

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC7A3	ENST00000374299.8	TSL:1 MANE Select	c.1766G>C	p.Ser589Thr	missense	Exon 12 of 12	ENSP00000363417.3	Q8WY07
	SLC7A3	ENST00000921007.1		c.1817G>C	p.Ser606Thr	missense	Exon 13 of 13	ENSP00000591066.1
	SLC7A3	ENST00000921008.1		c.1817G>C	p.Ser606Thr	missense	Exon 13 of 13	ENSP00000591067.1

Frequencies

GnomAD3 genomes AF: 0.00238 AC: 265 AN: 111456 Hom.: 1 Cov.: 23

Gnomad AFR AF: 0.000882

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00374

Gnomad ASJ AF: 0.00983

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000332

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00288

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00231 AC: 422 AN: 182326 AF XY: 0.00242

Gnomad AFR exome AF: 0.000760

Gnomad AMR exome AF: 0.00314

Gnomad ASJ exome AF: 0.00829

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000937

Gnomad NFE exome AF: 0.00279

Gnomad OTH exome AF: 0.00398

GnomAD4 exome AF: 0.00275 AC: 3025 AN: 1098150 Hom.: 6 Cov.: 31 AF XY: 0.00283 AC XY: 1029 AN XY: 363504

African (AFR) AF: 0.00117 AC: 31 AN: 26400

American (AMR) AF: 0.00307 AC: 108 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.0106 AC: 205 AN: 19384

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30205

South Asian (SAS) AF: 0.000222 AC: 12 AN: 54147

European-Finnish (FIN) AF: 0.000691 AC: 28 AN: 40532

Middle Eastern (MID) AF: 0.0123 AC: 51 AN: 4136

European-Non Finnish (NFE) AF: 0.00288 AC: 2428 AN: 842045

Other (OTH) AF: 0.00349 AC: 161 AN: 46095

GnomAD4 genome AF: 0.00237 AC: 264 AN: 111507 Hom.: 1 Cov.: 23 AF XY: 0.00237 AC XY: 80 AN XY: 33689

African (AFR) AF: 0.000880 AC: 27 AN: 30689

American (AMR) AF: 0.00374 AC: 39 AN: 10429

Ashkenazi Jewish (ASJ) AF: 0.00983 AC: 26 AN: 2644

East Asian (EAS) AF: 0.00 AC: 0 AN: 3544

South Asian (SAS) AF: 0.00 AC: 0 AN: 2613

European-Finnish (FIN) AF: 0.000332 AC: 2 AN: 6031

Middle Eastern (MID) AF: 0.0139 AC: 3 AN: 216

European-Non Finnish (NFE) AF: 0.00286 AC: 152 AN: 53138

Other (OTH) AF: 0.00988 AC: 15 AN: 1518

Alfa AF: 0.00368 Hom.: 85

Bravo AF: 0.00290

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00346 AC: 10

ESP6500AA AF: 0.000782 AC: 3

ESP6500EA AF: 0.00342 AC: 23

ExAC AF: 0.00240 AC: 291

EpiCase AF: 0.00431

EpiControl AF: 0.00510

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	SLC7A3-related disorder (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.42	D
MetaRNN	Benign	0.021	T
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		7.4
PrimateAI	Uncertain	0.48	T
PROVEAN	Uncertain	-2.5	D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.018	D
Polyphen		0.94	P
Vest4		0.71
MVP		0.94
MPC		0.81
ClinPred		0.027	T
GERP RS		4.8
Varity_R		0.68
gMVP		0.86
Mutation Taster		=34/66	disease causing (ClinVar)

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: rs149447856; hg19: chrX-70145757;