Genetic Variant SLC16A3:p.Arg216Ser (chr17-82237416-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004207.4(SLC16A3):c.646C>A(p.Arg216Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000705 in 1,418,526 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R216L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

SLC16A3
NM_004207.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.24

Publications

0 publications found

Variant links:

Genes affected

SLC16A3 (HGNC:10924): (solute carrier family 16 member 3) Lactic acid and pyruvate transport across plasma membranes is catalyzed by members of the proton-linked monocarboxylate transporter (MCT) family, which has been designated solute carrier family-16. Each MCT appears to have slightly different substrate and inhibitor specificities and transport kinetics, which are related to the metabolic requirements of the tissues in which it is found. The MCTs, which include MCT1 (SLC16A1; MIM 600682) and MCT2 (SLC16A7; MIM 603654), are characterized by 12 predicted transmembrane domains (Price et al., 1998 [PubMed 9425115]).[supplied by OMIM, Mar 2008]

SLC16A3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21480885).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC16A3	NM_004207.4 link	c.646C>A	p.Arg216Ser	missense_variant	Exon 4 of 5	ENST00000582743.6	NP_004198.1	O15427A0A024R8U1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC16A3	ENST00000582743.6 link	c.646C>A	p.Arg216Ser	missense_variant	Exon 4 of 5	1	NM_004207.4	ENSP00000462405.1		O15427

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.05e-7

AC:

AN:

1418526

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

702420

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32638

American (AMR)

AF:

0.0000254

AC:

AN:

39416

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25402

East Asian (EAS)

AF:

0.00

AC:

AN:

37614

South Asian (SAS)

AF:

0.00

AC:

AN:

82786

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45586

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5668

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1090782

Other (OTH)

AF:

0.00

AC:

AN:

58634

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.050

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.20

.;T;.;T;T;.;T;T;T;.;T;T

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.83

T;T;T;.;T;T;.;.;.;T;.;T

M_CAP

Benign

0.085

MetaRNN

Benign

0.21

T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.51

.;N;.;N;.;.;N;N;N;.;N;.

PhyloP100

3.2

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-2.4

.;N;.;.;.;.;N;.;.;.;.;.

REVEL

Benign

0.16

Sift

Benign

0.040

.;D;.;.;.;.;D;.;.;.;.;.

Sift4G

Uncertain

0.029

D;D;D;D;D;D;D;D;D;T;D;D

Polyphen

0.26

.;B;.;B;.;.;B;B;B;.;B;.

Vest4

0.43, 0.41, 0.46

MutPred

0.47

Gain of phosphorylation at R216 (P = 0.0209);Gain of phosphorylation at R216 (P = 0.0209);Gain of phosphorylation at R216 (P = 0.0209);Gain of phosphorylation at R216 (P = 0.0209);.;Gain of phosphorylation at R216 (P = 0.0209);Gain of phosphorylation at R216 (P = 0.0209);Gain of phosphorylation at R216 (P = 0.0209);Gain of phosphorylation at R216 (P = 0.0209);Gain of phosphorylation at R216 (P = 0.0209);Gain of phosphorylation at R216 (P = 0.0209);.;

MVP

0.56

MPC

0.44

ClinPred

0.71

GERP RS

1.5

PromoterAI

0.0092

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.14

gMVP

0.52

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over