NM_005495.3:c.1114G>A

Variant names:

• chr6-25776721-G-A
• rs11754288
• NM_005495.3:c.1114G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005495.3(SLC17A4):​c.1114G>A​(p.Ala372Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.396 in 1,613,594 control chromosomes in the GnomAD database, including 133,531 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 (★).

• Frequency:
  • Genomes: 𝑓 0.32 (9507 hom., cov: 31)
  • Exomes 𝑓: 0.40 (124024 hom.)
• Consequence: SLC17A4 NM_005495.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.465
• Publications: 64 publications found

Genes affected

SLC17A4 (HGNC:10932): (solute carrier family 17 member 4) Phosphate homeostasis is maintained by regulating intake, intestinal absorption, bone deposition and resorption, and renal excretion of phosphate. The central molecule in the control of phosphate excretion from the kidney is the sodium/phosphate cotransporter NPT1 (SLC17A1; MIM 182308), which is located in the renal proximal tubule. NPT1 uses the transmembrane electrochemical potential gradient of sodium to transport phosphate across the cell membrane. SLC17A4 is a similar sodium/phosphate cotransporter in the intestinal mucosa that plays an important role in the absorption of phosphate from the intestine (summary by Shibui et al., 1999 [PubMed 10319585]).[supplied by OMIM, Feb 2011]

SLC17A1 (HGNC:10929): (solute carrier family 17 member 1) Predicted to enable sialic acid transmembrane transporter activity. Involved in urate metabolic process and urate transport. Located in apical plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.5436282E-4).
• BP6: Variant 6-25776721-G-A is Benign according to our data. Variant chr6-25776721-G-A is described in ClinVar as Benign. ClinVar VariationId is 1229422.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.434 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC17A4	NM_005495.3	c.1114G>A	p.Ala372Thr	missense_variant	Exon 9 of 12	ENST00000377905.9	NP_005486.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC17A4	ENST00000377905.9	c.1114G>A	p.Ala372Thr	missense_variant	Exon 9 of 12	1	NM_005495.3	ENSP00000367137.4
SLC17A4	ENST00000439485.6	c.952G>A	p.Ala318Thr	missense_variant	Exon 10 of 13	5		ENSP00000391345.3
SLC17A4	ENST00000397076.2	c.424G>A	p.Ala142Thr	missense_variant	Exon 5 of 7	2		ENSP00000380266.2

Frequencies

GnomAD3 genomes AF: 0.319 AC: 48511 AN: 151888 Hom.: 9510 Cov.: 31

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.652

Gnomad AMR AF: 0.328

Gnomad ASJ AF: 0.510

Gnomad EAS AF: 0.159

Gnomad SAS AF: 0.449

Gnomad FIN AF: 0.339

Gnomad MID AF: 0.415

Gnomad NFE AF: 0.435

Gnomad OTH AF: 0.322

GnomAD2 exomes AF: 0.364 AC: 91384 AN: 250786 AF XY: 0.381

Gnomad AFR exome AF: 0.0952

Gnomad AMR exome AF: 0.261

Gnomad ASJ exome AF: 0.495

Gnomad EAS exome AF: 0.130

Gnomad FIN exome AF: 0.352

Gnomad NFE exome AF: 0.437

Gnomad OTH exome AF: 0.403

GnomAD4 exome AF: 0.404 AC: 590264 AN: 1461592 Hom.: 124024 Cov.: 56 AF XY: 0.408 AC XY: 296630 AN XY: 727086

African (AFR) AF: 0.0858 AC: 2871 AN: 33462

American (AMR) AF: 0.273 AC: 12210 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.484 AC: 12634 AN: 26124

East Asian (EAS) AF: 0.150 AC: 5945 AN: 39692

South Asian (SAS) AF: 0.450 AC: 38845 AN: 86244

European-Finnish (FIN) AF: 0.353 AC: 18862 AN: 53416

Middle Eastern (MID) AF: 0.398 AC: 2292 AN: 5766

European-Non Finnish (NFE) AF: 0.426 AC: 473357 AN: 1111810

Other (OTH) AF: 0.385 AC: 23248 AN: 60382

GnomAD4 genome AF: 0.319 AC: 48508 AN: 152002 Hom.: 9507 Cov.: 31 AF XY: 0.318 AC XY: 23589 AN XY: 74280

African (AFR) AF: 0.102 AC: 4230 AN: 41486

American (AMR) AF: 0.328 AC: 5007 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.510 AC: 1767 AN: 3468

East Asian (EAS) AF: 0.160 AC: 824 AN: 5158

South Asian (SAS) AF: 0.449 AC: 2162 AN: 4810

European-Finnish (FIN) AF: 0.339 AC: 3576 AN: 10556

Middle Eastern (MID) AF: 0.418 AC: 123 AN: 294

European-Non Finnish (NFE) AF: 0.435 AC: 29544 AN: 67932

Other (OTH) AF: 0.322 AC: 680 AN: 2112

Alfa AF: 0.399 Hom.: 60765

Bravo AF: 0.302

TwinsUK AF: 0.427 AC: 1584

ALSPAC AF: 0.434 AC: 1671

ESP6500AA AF: 0.111 AC: 490

ESP6500EA AF: 0.440 AC: 3781

ExAC AF: 0.367 AC: 44545

Asia WGS AF: 0.307 AC: 1065 AN: 3478

EpiCase AF: 0.442

EpiControl AF: 0.452

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jan 18, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30315176) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Benign	0.074	.;T;.
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.58	T;T;T
MetaRNN	Benign	0.00025	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.53	.;N;.
PhyloP100		0.47
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.87	.;N;N
REVEL	Benign	0.082
Sift	Benign	0.49	.;T;T
Sift4G	Benign	0.44	T;T;T
Polyphen		0.0030	.;B;.
Vest4		0.050
MPC		0.10
ClinPred		0.0018	T
GERP RS		-2.3
Varity_R		0.096
gMVP		0.16
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs11754288; hg19: chr6-25776949; COSMIC: COSV64955869;