Genetic Variant SLC67A1:p.Arg89Leu (chr11-2909219-G-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_002555.6(SLC67A1):c.266G>T(p.Arg89Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. R89P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 35)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SLC67A1
NM_002555.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.81

Publications

0 publications found

Variant links:

Genes affected

SLC67A1 (HGNC:10964): (solute carrier family 22 member 18) This gene is one of several tumor-suppressing subtransferable fragments located in the imprinted gene domain of 11p15.5, an important tumor-suppressor gene region. Alterations in this region have been associated with the Beckwith-Wiedemann syndrome, Wilms tumor, rhabdomyosarcoma, adrenocortical carcinoma, and lung, ovarian, and breast cancer. This gene is imprinted, with preferential expression from the maternal allele. Mutations in this gene have been found in Wilms' tumor and lung cancer. This protein may act as a transporter of organic cations, and have a role in the transport of chloroquine and quinidine-related compounds in kidney. Several alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Oct 2015]

SLC67A1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.965

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002555.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SLC67A1	NM_002555.6	MANE Select	c.266G>T	p.Arg89Leu	missense	Exon 4 of 11	NP_002546.3
SLC67A1	NM_001315501.2		c.521G>T	p.Arg174Leu	missense	Exon 4 of 11	NP_001302430.1
SLC67A1	NM_183233.3		c.266G>T	p.Arg89Leu	missense	Exon 4 of 11	NP_899056.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC67A1	ENST00000649076.2	MANE Select	c.266G>T	p.Arg89Leu	missense	Exon 4 of 11	ENSP00000497561.1	Q96BI1
SLC67A1	ENST00000347936.6	TSL:1	c.266G>T	p.Arg89Leu	missense	Exon 4 of 11	ENSP00000307859.2	Q96BI1
SLC67A1	ENST00000380574.5	TSL:1	c.266G>T	p.Arg89Leu	missense	Exon 4 of 11	ENSP00000369948.1	Q96BI1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1386780

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

685010

African (AFR)

AF:

0.00

AC:

AN:

31226

American (AMR)

AF:

0.00

AC:

AN:

36758

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24954

East Asian (EAS)

AF:

0.00

AC:

AN:

36270

South Asian (SAS)

AF:

0.00

AC:

AN:

79008

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34830

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5226

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1080692

Other (OTH)

AF:

0.00

AC:

AN:

57816

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

Eigen

Uncertain

0.32

Eigen_PC

Benign

0.11

FATHMM_MKL

Benign

0.38

LIST_S2

Uncertain

0.92

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

-0.18

MutationAssessor

Uncertain

2.9

PhyloP100

2.8

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-5.8

REVEL

Uncertain

0.40

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0080

Polyphen

1.0

Vest4

0.61

MutPred

0.88

Loss of methylation at R89 (P = 0.0107)

MVP

0.84

MPC

0.77

ClinPred

0.99

GERP RS

2.1

Varity_R

0.76

gMVP

0.65

Mutation Taster

=74/26

polymorphism

(source)

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over