chr11-2909599-A-T

Variant names:

• chr11-2909599-A-T
• rs543432257
• NM_002555.6:c.425A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_002555.6(SLC67A1):​c.425A>T​(p.Asp142Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000218 in 1,378,474 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D142G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: SLC67A1 NM_002555.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.57
• Publications: 0 publications found

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]

ACMG classification

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, 0.949

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC67A1	NM_002555.6	MANE Select	c.425A>T	p.Asp142Val	missense	Exon 5 of 11	NP_002546.3
	SLC67A1	NM_001315501.2		c.680A>T	p.Asp227Val	missense	Exon 5 of 11	NP_001302430.1
	SLC67A1	NM_183233.3		c.425A>T	p.Asp142Val	missense	Exon 5 of 11	NP_899056.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC67A1	ENST00000649076.2	MANE Select	c.425A>T	p.Asp142Val	missense	Exon 5 of 11	ENSP00000497561.1	Q96BI1
	SLC67A1	ENST00000347936.6	TSL:1	c.425A>T	p.Asp142Val	missense	Exon 5 of 11	ENSP00000307859.2	Q96BI1
	SLC67A1	ENST00000380574.5	TSL:1	c.425A>T	p.Asp142Val	missense	Exon 5 of 11	ENSP00000369948.1	Q96BI1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000218 AC: 3 AN: 1378474 Hom.: 0 Cov.: 35 AF XY: 0.00000294 AC XY: 2 AN XY: 680354

African (AFR) AF: 0.00 AC: 0 AN: 30454

American (AMR) AF: 0.00 AC: 0 AN: 35394

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24848

East Asian (EAS) AF: 0.00 AC: 0 AN: 34998

South Asian (SAS) AF: 0.00 AC: 0 AN: 78730

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35440

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4776

European-Non Finnish (NFE) AF: 0.00000279 AC: 3 AN: 1076322

Other (OTH) AF: 0.00 AC: 0 AN: 57512

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.10
FATHMM_MKL	Benign	0.35	N
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.086	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Benign	-0.33	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		1.6
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.7	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.76
MutPred		0.85		Loss of disorder (P = 0.0534)
MVP		0.75
MPC		0.84
ClinPred		0.99	D
GERP RS		2.9
Varity_R		0.86
gMVP		0.79
Mutation Taster		=79/21	polymorphism

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: rs543432257; hg19: chr11-2930829;