chr12-50992810-C-G

Position:

• chr12-50992810-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000262052.9(SLC11A2):​c.1197G>C​(p.Glu399Asp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000186 in 1,613,564 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E399K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 30)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SLC11A2 ENST00000262052.9 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 5.25

Genes affected

SLC11A2 (HGNC:10908): (solute carrier family 11 member 2) This gene encodes a member of the solute carrier family 11 protein family. The product of this gene transports divalent metals and is involved in iron absorption. Mutations in this gene are associated with hypochromic microcytic anemia with iron overload. A related solute carrier family 11 protein gene is located on chromosome 2. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Apr 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC11A2	NM_000617.3	c.1197G>C	p.Glu399Asp	missense_variant, splice_region_variant	12/16	ENST00000262052.9	NP_000608.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC11A2	ENST00000262052.9	c.1197G>C	p.Glu399Asp	missense_variant, splice_region_variant	12/16	1	NM_000617.3	ENSP00000262052

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151832 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461732 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727180

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151832 Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1 AN XY: 74122

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Microcytic anemia with liver iron overload Pathogenic:1 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2005	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 17, 2018	The SLC11A2 c.1197G>C (p.Glu399Asp) variant is a missense variant that occurs in a splice region. It was identified in a single homozygous individual with hypochromic microcytic anemia with iron overload (Mims et al. 2005; Lam-Yuk-Tseung et al. 2005; Priwitzerova et al. 2005; Gunshin et al. 2005). The unaffected parents and sibling of the affected individual were confirmed carriers of the variant. The p.Glu399Asp variant was absent from 108 healthy controls and is reported at a frequency of 0.000067 in the European (non-Finnish) population of the Genome Aggregation Database. This frequency is based on one allele in a region of good sequencing coverage, so the variant is presumed to be rare. In addition to resulting in a full-length transcript containing a p.Glu399Asp amino acid substitution, this variant, which is also described as c.1285G>C, also disrupts normal splicing of pre-mRNA, leading to skipping of exon 12. Various methods of functional testing indicated that the full-length protein with the p.Glu399Asp variant behaved comparably to the wild type protein, whereas the protein lacking exon 12 was non-functional (Lam-Yuk-Tseung et al. 2005; Priwitzerova et al. 2005). Based on the available evidence, the p.Glu399Asp variant is classified as a variant of uncertain significance but suspicious for pathogenicity for hypochromic microcytic anemia with iron overload. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;D;.;D;.;.;.;.;.;.;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	.;.;D;D;.;.;.;D;D;D;D
M_CAP	Uncertain	0.096	D
MetaRNN	Uncertain	0.74	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Pathogenic	3.0	M;M;.;M;M;M;.;M;.;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.9	D;.;.;D;D;.;D;D;D;D;D
REVEL	Pathogenic	0.69
Sift	Benign	0.030	D;.;.;D;D;.;D;D;D;D;D
Sift4G	Uncertain	0.049	D;.;.;D;D;.;D;D;D;D;D
Polyphen		0.98	D;D;.;D;P;P;D;P;.;.;D
Vest4		0.60
MutPred		0.72		Gain of catalytic residue at Q395 (P = 2e-04);Gain of catalytic residue at Q395 (P = 2e-04);.;Gain of catalytic residue at Q395 (P = 2e-04);Gain of catalytic residue at Q395 (P = 2e-04);Gain of catalytic residue at Q395 (P = 2e-04);.;Gain of catalytic residue at Q395 (P = 2e-04);.;.;.;
MVP		0.93
MPC		1.3
ClinPred		0.96	D
GERP RS		4.3
Varity_R		0.75
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.49		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.49		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121918365; hg19: chr12-51386593;