NM_000617.3:c.1254T>C

Variant names:

• chr12-50992283-A-G
• rs1048230
• NM_000617.3:c.1254T>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000617.3(SLC11A2):​c.1254T>C​(p.Ile418Ile) 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
• Publications: 37 publications found

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]

SLC11A2 Gene-Disease associations (from GenCC):

• microcytic anemia with liver iron overload

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Ambry Genetics, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 309312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000617.3. 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
	SLC11A2	NM_000617.3	MANE Select	c.1254T>C	p.Ile418Ile	synonymous	Exon 13 of 16	NP_000608.1	P49281-2
	SLC11A2	NM_001379446.1		c.1341T>C	p.Ile447Ile	synonymous	Exon 13 of 17	NP_001366375.1	P49281-4
	SLC11A2	NM_001174125.2		c.1341T>C	p.Ile447Ile	synonymous	Exon 13 of 16	NP_001167596.1	P49281-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC11A2	ENST00000262052.9	TSL:1 MANE Select	c.1254T>C	p.Ile418Ile	synonymous	Exon 13 of 16	ENSP00000262052.5	P49281-2
	SLC11A2	ENST00000394904.9	TSL:1	c.1341T>C	p.Ile447Ile	synonymous	Exon 13 of 16	ENSP00000378364.3	P49281-3
	SLC11A2	ENST00000547198.5	TSL:1	c.1254T>C	p.Ile418Ile	synonymous	Exon 13 of 17	ENSP00000446769.1	P49281-1

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

GnomAD2 exomes AF: 0.170 AC: 42673 AN: 251356 AF XY: 0.180

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 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

African (AFR) AF: 0.0684 AC: 2289 AN: 33474

American (AMR) AF: 0.114 AC: 5098 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.169 AC: 4428 AN: 26136

East Asian (EAS) AF: 0.106 AC: 4226 AN: 39692

South Asian (SAS) AF: 0.277 AC: 23891 AN: 86242

European-Finnish (FIN) AF: 0.159 AC: 8486 AN: 53414

Middle Eastern (MID) AF: 0.266 AC: 1530 AN: 5760

European-Non Finnish (NFE) AF: 0.192 AC: 213364 AN: 1111554

Other (OTH) AF: 0.187 AC: 11318 AN: 60366

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

African (AFR) AF: 0.0718 AC: 2983 AN: 41550

American (AMR) AF: 0.129 AC: 1965 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 567 AN: 3468

East Asian (EAS) AF: 0.115 AC: 594 AN: 5180

South Asian (SAS) AF: 0.265 AC: 1278 AN: 4824

European-Finnish (FIN) AF: 0.152 AC: 1605 AN: 10582

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.189 AC: 12831 AN: 67976

Other (OTH) AF: 0.165 AC: 348 AN: 2108

Alfa AF: 0.170 Hom.: 3682

Bravo AF: 0.137

Asia WGS AF: 0.159 AC: 550 AN: 3478

EpiCase AF: 0.185

EpiControl AF: 0.188

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Microcytic anemia with liver iron overload (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	8.3
DANN	Benign	0.74
PhyloP100		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=93/7	polymorphism (auto)

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

Other links and lift over

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