rs1048230

Positions:

• chr12-50992283-A-G
• chr12-50992283-A-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000617.3(SLC11A2):​c.1254T>C​(p.Ile418=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.184 in 1,613,532 control chromosomes in the GnomAD database, including 28,932 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1881 hom., cov: 32)
  • Exomes 𝑓: 0.19 (27051 hom.)
• Consequence: SLC11A2 NM_000617.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.87

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 Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 12-50992283-A-G is Benign according to our data. Variant chr12-50992283-A-G is described in ClinVar as [Benign]. Clinvar id is 309312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-50992283-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.87 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.253 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC11A2	NM_000617.3	c.1254T>C	p.Ile418=	synonymous_variant	13/16	ENST00000262052.9	NP_000608.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC11A2	ENST00000262052.9	c.1254T>C	p.Ile418=	synonymous_variant	13/16	1	NM_000617.3	ENSP00000262052

Frequencies

GnomAD3 genomes AF: 0.147 AC: 22395 AN: 152052 Hom.: 1876 Cov.: 32

Gnomad AFR AF: 0.0720

Gnomad AMI AF: 0.193

Gnomad AMR AF: 0.128

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.115

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.152

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.189

Gnomad OTH AF: 0.166

GnomAD3 exomes AF: 0.170 AC: 42673 AN: 251356 Hom.: 4082 AF XY: 0.180 AC XY: 24382 AN XY: 135832

Gnomad AFR exome AF: 0.0665

Gnomad AMR exome AF: 0.112

Gnomad ASJ exome AF: 0.169

Gnomad EAS exome AF: 0.113

Gnomad SAS exome AF: 0.279

Gnomad FIN exome AF: 0.156

Gnomad NFE exome AF: 0.183

Gnomad OTH exome AF: 0.196

GnomAD4 exome AF: 0.188 AC: 274630 AN: 1461362 Hom.: 27051 Cov.: 33 AF XY: 0.191 AC XY: 139152 AN XY: 727000

Gnomad4 AFR exome AF: 0.0684

Gnomad4 AMR exome AF: 0.114

Gnomad4 ASJ exome AF: 0.169

Gnomad4 EAS exome AF: 0.106

Gnomad4 SAS exome AF: 0.277

Gnomad4 FIN exome AF: 0.159

Gnomad4 NFE exome AF: 0.192

Gnomad4 OTH exome AF: 0.187

GnomAD4 genome AF: 0.147 AC: 22403 AN: 152170 Hom.: 1881 Cov.: 32 AF XY: 0.147 AC XY: 10948 AN XY: 74394

Gnomad4 AFR AF: 0.0718

Gnomad4 AMR AF: 0.129

Gnomad4 ASJ AF: 0.163

Gnomad4 EAS AF: 0.115

Gnomad4 SAS AF: 0.265

Gnomad4 FIN AF: 0.152

Gnomad4 NFE AF: 0.189

Gnomad4 OTH AF: 0.165

Alfa AF: 0.174 Hom.: 3150

Bravo AF: 0.137

Asia WGS AF: 0.159 AC: 550 AN: 3478

EpiCase AF: 0.185

EpiControl AF: 0.188

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Microcytic anemia with liver iron overload Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	8.3
DANN	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

LitVar

Other links and lift over

dbSNP: rs1048230; hg19: chr12-51386066; COSMIC: COSV50369968; COSMIC: COSV50369968;