Genetic Variant SLC16A1:p.Asn147Lys (chr1-112917965-G-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_003051.4(SLC16A1):c.441C>A(p.Asn147Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000697 in 1,434,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N147N) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

SLC16A1
NM_003051.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.75

Publications

0 publications found

Variant links:

Genes affected

SLC16A1 (HGNC:10922): (solute carrier family 16 member 1) The protein encoded by this gene is a proton-linked monocarboxylate transporter that catalyzes the movement of many monocarboxylates, such as lactate and pyruvate, across the plasma membrane. Mutations in this gene are associated with erythrocyte lactate transporter defect. Alternatively spliced transcript variants have been found for this gene.[provided by RefSeq, Oct 2009]

SLC16A1 links:

SLC16A1-AS1 (HGNC:49445): (SLC16A1 antisense RNA 1)

SLC16A1-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.844

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC16A1	NM_003051.4 link	c.441C>A	p.Asn147Lys	missense_variant	Exon 4 of 5	ENST00000369626.8	NP_003042.3	P53985-1A0A024R0H1
SLC16A1	NM_001166496.2 link	c.441C>A	p.Asn147Lys	missense_variant	Exon 4 of 5		NP_001159968.1	P53985-1A0A024R0H1B4DKS0
SLC16A1	XM_047428789.1 link	c.441C>A	p.Asn147Lys	missense_variant	Exon 4 of 5		XP_047284745.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC16A1	ENST00000369626.8 link	c.441C>A	p.Asn147Lys	missense_variant	Exon 4 of 5	1	NM_003051.4	ENSP00000358640.4		P53985-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.97e-7

AC:

AN:

1434662

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

713186

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:

31566

American (AMR)

AF:

0.00

AC:

AN:

36162

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24406

East Asian (EAS)

AF:

0.00

AC:

AN:

39626

South Asian (SAS)

AF:

0.00

AC:

AN:

80578

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5592

European-Non Finnish (NFE)

AF:

9.05e-7

AC:

AN:

1105034

Other (OTH)

AF:

0.00

AC:

AN:

59098

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Benign

-0.015

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.72

D;D;D;T;T

Eigen

Uncertain

0.27

Eigen_PC

Benign

0.10

FATHMM_MKL

Uncertain

0.79

M_CAP

Benign

0.044

MetaRNN

Pathogenic

0.84

D;D;D;D;D

MetaSVM

Benign

-0.45

MutationAssessor

Pathogenic

3.7

H;H;.;.;.

PhyloP100

1.8

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-5.6

D;D;D;D;D

REVEL

Uncertain

0.45

Sift

Uncertain

0.0010

D;D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;.;.;.

Polyphen

1.0

D;D;.;.;.

Vest4

0.97

MutPred

0.73

Gain of ubiquitination at N147 (P = 0.0289);Gain of ubiquitination at N147 (P = 0.0289);Gain of ubiquitination at N147 (P = 0.0289);Gain of ubiquitination at N147 (P = 0.0289);Gain of ubiquitination at N147 (P = 0.0289);

MVP

0.79

MPC

1.1

ClinPred

0.98

GERP RS

1.9

Varity_R

0.97

gMVP

0.91

Mutation Taster

=27/73

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over