rs4646227

Positions:

• chr13-98706147-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005073.4(SLC15A1):​c.1256G>C​(p.Gly419Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.029 in 1,610,572 control chromosomes in the GnomAD database, including 1,191 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.048 (304 hom., cov: 32)
  • Exomes 𝑓: 0.027 (887 hom.)
• Consequence: SLC15A1 NM_005073.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.28

Genes affected

SLC15A1 (HGNC:10920): (solute carrier family 15 member 1) This gene encodes an intestinal hydrogen peptide cotransporter that is a member of the solute carrier family 15. The encoded protein is localized to the brush border membrane of the intestinal epithelium and mediates the uptake of di- and tripeptides from the lumen into the enterocytes. This protein plays an important role in the uptake and digestion of dietary proteins. This protein also facilitates the absorption of numerous peptidomimetic drugs. [provided by RefSeq, Apr 2010]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015791059).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC15A1	NM_005073.4	c.1256G>C	p.Gly419Ala	missense_variant	16/23	ENST00000376503.10	NP_005064.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC15A1	ENST00000376503.10	c.1256G>C	p.Gly419Ala	missense_variant	16/23	1	NM_005073.4	ENSP00000365686	P1

Frequencies

GnomAD3 genomes AF: 0.0483 AC: 7347 AN: 152106 Hom.: 298 Cov.: 32

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0305

Gnomad ASJ AF: 0.0570

Gnomad EAS AF: 0.0817

Gnomad SAS AF: 0.0795

Gnomad FIN AF: 0.00368

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0201

Gnomad OTH AF: 0.0498

GnomAD3 exomes AF: 0.0377 AC: 9347 AN: 248240 Hom.: 312 AF XY: 0.0380 AC XY: 5088 AN XY: 133964

Gnomad AFR exome AF: 0.110

Gnomad AMR exome AF: 0.0197

Gnomad ASJ exome AF: 0.0585

Gnomad EAS exome AF: 0.0818

Gnomad SAS exome AF: 0.0736

Gnomad FIN exome AF: 0.00324

Gnomad NFE exome AF: 0.0210

Gnomad OTH exome AF: 0.0358

GnomAD4 exome AF: 0.0270 AC: 39394 AN: 1458348 Hom.: 887 Cov.: 31 AF XY: 0.0281 AC XY: 20349 AN XY: 725210

Gnomad4 AFR exome AF: 0.109

Gnomad4 AMR exome AF: 0.0212

Gnomad4 ASJ exome AF: 0.0612

Gnomad4 EAS exome AF: 0.0573

Gnomad4 SAS exome AF: 0.0718

Gnomad4 FIN exome AF: 0.00444

Gnomad4 NFE exome AF: 0.0198

Gnomad4 OTH exome AF: 0.0384

GnomAD4 genome AF: 0.0485 AC: 7376 AN: 152224 Hom.: 304 Cov.: 32 AF XY: 0.0471 AC XY: 3509 AN XY: 74456

Gnomad4 AFR AF: 0.106

Gnomad4 AMR AF: 0.0304

Gnomad4 ASJ AF: 0.0570

Gnomad4 EAS AF: 0.0821

Gnomad4 SAS AF: 0.0792

Gnomad4 FIN AF: 0.00368

Gnomad4 NFE AF: 0.0201

Gnomad4 OTH AF: 0.0483

Alfa AF: 0.0284 Hom.: 75

Bravo AF: 0.0521

TwinsUK AF: 0.0183 AC: 68

ALSPAC AF: 0.0192 AC: 74

ESP6500AA AF: 0.111 AC: 490

ESP6500EA AF: 0.0207 AC: 178

ExAC AF: 0.0391 AC: 4745

Asia WGS AF: 0.0800 AC: 276 AN: 3478

EpiCase AF: 0.0249

EpiControl AF: 0.0247

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.0010
DANN	Benign	0.17
DEOGEN2	Benign	0.039	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0085	N
LIST_S2	Benign	0.19	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.36	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.50	N
REVEL	Benign	0.010
Sift	Benign	0.81	T
Sift4G	Benign	0.75	T
Polyphen		0.0	B
Vest4		0.035
MPC		0.048
ClinPred		0.0025	T
GERP RS		-9.3
Varity_R		0.024
gMVP		0.48

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: rs4646227; hg19: chr13-99358401; COSMIC: COSV64731622;