NM_003045.5:c.1522A>G

Variant names:

• chr13-29517299-T-C
• rs75759022
• NM_003045.5:c.1522A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003045.5(SLC7A1):​c.1522A>G​(p.Ile508Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00218 in 1,610,986 control chromosomes in the GnomAD database, including 65 homozygotes. 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I508T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (33 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (32 hom.)
• Consequence: SLC7A1 NM_003045.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.10
• Publications: 2 publications found

Genes affected

SLC7A1 (HGNC:11057): (solute carrier family 7 member 1) Enables L-arginine transmembrane transporter activity and L-histidine transmembrane transporter activity. Involved in amino acid transport. Located in membrane. Part of apical plasma membrane; basolateral plasma membrane; and protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019243956).
• BP6: Variant 13-29517299-T-C is Benign according to our data. Variant chr13-29517299-T-C is described in ClinVar as Benign. ClinVar VariationId is 781099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.012 (1829/152288) while in subpopulation AFR AF = 0.0424 (1763/41554). AF 95% confidence interval is 0.0408. There are 33 homozygotes in GnomAd4. There are 875 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 33 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003045.5. 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
	SLC7A1	NM_003045.5	MANE Select	c.1522A>G	p.Ile508Val	missense	Exon 11 of 13	NP_003036.1	P30825

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC7A1	ENST00000380752.10	TSL:1 MANE Select	c.1522A>G	p.Ile508Val	missense	Exon 11 of 13	ENSP00000370128.5	P30825
	SLC7A1	ENST00000936269.1		c.1684A>G	p.Ile562Val	missense	Exon 12 of 14	ENSP00000606328.1
	SLC7A1	ENST00000936271.1		c.1546A>G	p.Ile516Val	missense	Exon 11 of 13	ENSP00000606330.1

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1826 AN: 152170 Hom.: 32 Cov.: 33

Gnomad AFR AF: 0.0425

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00290 AC: 712 AN: 245916 AF XY: 0.00220

Gnomad AFR exome AF: 0.0413

Gnomad AMR exome AF: 0.00134

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000269

Gnomad OTH exome AF: 0.00168

GnomAD4 exome AF: 0.00115 AC: 1676 AN: 1458698 Hom.: 32 Cov.: 31 AF XY: 0.000966 AC XY: 701 AN XY: 725564

African (AFR) AF: 0.0438 AC: 1459 AN: 33322

American (AMR) AF: 0.00150 AC: 66 AN: 44048

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25940

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.0000468 AC: 4 AN: 85502

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53262

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1110940

Other (OTH) AF: 0.00224 AC: 135 AN: 60248

GnomAD4 genome AF: 0.0120 AC: 1829 AN: 152288 Hom.: 33 Cov.: 33 AF XY: 0.0117 AC XY: 875 AN XY: 74476

African (AFR) AF: 0.0424 AC: 1763 AN: 41554

American (AMR) AF: 0.00359 AC: 55 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68024

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.0199 Hom.: 2293

Bravo AF: 0.0136

ESP6500AA AF: 0.0359 AC: 158

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00371 AC: 451

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.51
DANN	Benign	0.36
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		-1.1
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.13
Sift	Benign	0.90	T
Sift4G	Benign	0.61	T
Polyphen		0.0	B
Vest4		0.066
MVP		0.47
MPC		0.64
ClinPred		0.0047	T
GERP RS		-0.95
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.023
gMVP		0.17
Mutation Taster		=99/1	polymorphism

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: rs75759022; hg19: chr13-30091436;