rs149411

Variant names:

• chr12-50986449-A-G
• rs149411
• NM_000617.3:c.*1876T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000617.3(SLC11A2):​c.*1876T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.564 in 1,283,976 control chromosomes in the GnomAD database, including 208,786 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (21912 hom., cov: 32)
  • Exomes 𝑓: 0.57 (186874 hom.)
• Consequence: SLC11A2 NM_000617.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.274
• Publications: 20 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: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 12-50986449-A-G is Benign according to our data. Variant chr12-50986449-A-G is described in ClinVar as Benign. ClinVar VariationId is 309281.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.616 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC11A2	NM_000617.3	c.*1876T>C		3_prime_UTR_variant	Exon 16 of 16	ENST00000262052.9	NP_000608.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC11A2	ENST00000262052.9	c.*1876T>C		3_prime_UTR_variant	Exon 16 of 16	1	NM_000617.3	ENSP00000262052.5

Frequencies

GnomAD3 genomes AF: 0.525 AC: 79695 AN: 151848 Hom.: 21905 Cov.: 32

Gnomad AFR AF: 0.382

Gnomad AMI AF: 0.392

Gnomad AMR AF: 0.626

Gnomad ASJ AF: 0.571

Gnomad EAS AF: 0.372

Gnomad SAS AF: 0.355

Gnomad FIN AF: 0.641

Gnomad MID AF: 0.456

Gnomad NFE AF: 0.594

Gnomad OTH AF: 0.538

GnomAD2 exomes AF: 0.543 AC: 69862 AN: 128744 AF XY: 0.525

Gnomad AFR exome AF: 0.376

Gnomad AMR exome AF: 0.677

Gnomad ASJ exome AF: 0.580

Gnomad EAS exome AF: 0.366

Gnomad FIN exome AF: 0.641

Gnomad NFE exome AF: 0.598

Gnomad OTH exome AF: 0.550

GnomAD4 exome AF: 0.569 AC: 644075 AN: 1132010 Hom.: 186874 Cov.: 32 AF XY: 0.562 AC XY: 312148 AN XY: 555408

African (AFR) AF: 0.358 AC: 8679 AN: 24260

American (AMR) AF: 0.676 AC: 19052 AN: 28172

Ashkenazi Jewish (ASJ) AF: 0.576 AC: 9169 AN: 15906

East Asian (EAS) AF: 0.369 AC: 4730 AN: 12816

South Asian (SAS) AF: 0.367 AC: 27903 AN: 75928

European-Finnish (FIN) AF: 0.632 AC: 7989 AN: 12638

Middle Eastern (MID) AF: 0.465 AC: 1286 AN: 2764

European-Non Finnish (NFE) AF: 0.591 AC: 542870 AN: 918288

Other (OTH) AF: 0.543 AC: 22397 AN: 41238

GnomAD4 genome AF: 0.525 AC: 79731 AN: 151966 Hom.: 21912 Cov.: 32 AF XY: 0.525 AC XY: 38962 AN XY: 74284

African (AFR) AF: 0.381 AC: 15826 AN: 41492

American (AMR) AF: 0.626 AC: 9563 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.571 AC: 1983 AN: 3470

East Asian (EAS) AF: 0.372 AC: 1927 AN: 5182

South Asian (SAS) AF: 0.354 AC: 1707 AN: 4816

European-Finnish (FIN) AF: 0.641 AC: 6771 AN: 10566

Middle Eastern (MID) AF: 0.449 AC: 132 AN: 294

European-Non Finnish (NFE) AF: 0.594 AC: 40328 AN: 67854

Other (OTH) AF: 0.539 AC: 1138 AN: 2110

Alfa AF: 0.573 Hom.: 108922

Bravo AF: 0.522

Asia WGS AF: 0.408 AC: 1416 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Microcytic anemia with liver iron overload Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.82
CADD	Benign	6.4
DANN	Benign	0.66
PhyloP100		0.27
Mutation Taster		=100/0	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: rs149411; hg19: chr12-51380232;