12-51026381-C-A

Variant names:

• chr12-51026381-C-A
• rs6580779
• NM_000617.3:c.-110G>T

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.-110G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.932 in 1,277,586 control chromosomes in the GnomAD database, including 555,325 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.91 (63297 hom., cov: 33)
  • Exomes 𝑓: 0.93 (492028 hom.)
• Consequence: SLC11A2 NM_000617.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.252
• Publications: 9 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=-0.74).
• BP6: Variant 12-51026381-C-A is Benign according to our data. Variant chr12-51026381-C-A is described in ClinVar as [Benign]. Clinvar id is 309328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.962 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC11A2	NM_000617.3	c.-110G>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 16	ENST00000262052.9	NP_000608.1
SLC11A2	NM_000617.3	c.-110G>T		5_prime_UTR_variant	Exon 1 of 16	ENST00000262052.9	NP_000608.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC11A2	ENST00000262052.9	c.-110G>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 16	1	NM_000617.3	ENSP00000262052.5
SLC11A2	ENST00000262052.9	c.-110G>T		5_prime_UTR_variant	Exon 1 of 16	1	NM_000617.3	ENSP00000262052.5

Frequencies

GnomAD3 genomes AF: 0.910 AC: 138373 AN: 152090 Hom.: 63231 Cov.: 33

Gnomad AFR AF: 0.815

Gnomad AMI AF: 0.920

Gnomad AMR AF: 0.940

Gnomad ASJ AF: 0.938

Gnomad EAS AF: 0.984

Gnomad SAS AF: 0.906

Gnomad FIN AF: 0.982

Gnomad MID AF: 0.905

Gnomad NFE AF: 0.942

Gnomad OTH AF: 0.920

GnomAD2 exomes AF: 0.938 AC: 120163 AN: 128156 AF XY: 0.935

Gnomad AFR exome AF: 0.811

Gnomad AMR exome AF: 0.959

Gnomad ASJ exome AF: 0.947

Gnomad EAS exome AF: 0.981

Gnomad FIN exome AF: 0.979

Gnomad NFE exome AF: 0.940

Gnomad OTH exome AF: 0.940

GnomAD4 exome AF: 0.935 AC: 1051852 AN: 1125378 Hom.: 492028 Cov.: 25 AF XY: 0.934 AC XY: 516135 AN XY: 552314

African (AFR) AF: 0.797 AC: 19144 AN: 24022

American (AMR) AF: 0.959 AC: 26894 AN: 28034

Ashkenazi Jewish (ASJ) AF: 0.949 AC: 15012 AN: 15820

East Asian (EAS) AF: 0.981 AC: 12423 AN: 12660

South Asian (SAS) AF: 0.908 AC: 68778 AN: 75716

European-Finnish (FIN) AF: 0.977 AC: 12342 AN: 12634

Middle Eastern (MID) AF: 0.904 AC: 2485 AN: 2748

European-Non Finnish (NFE) AF: 0.938 AC: 856618 AN: 912758

Other (OTH) AF: 0.931 AC: 38156 AN: 40986

GnomAD4 genome AF: 0.910 AC: 138496 AN: 152208 Hom.: 63297 Cov.: 33 AF XY: 0.914 AC XY: 68038 AN XY: 74420

African (AFR) AF: 0.816 AC: 33867 AN: 41518

American (AMR) AF: 0.940 AC: 14395 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.938 AC: 3258 AN: 3472

East Asian (EAS) AF: 0.984 AC: 5069 AN: 5150

South Asian (SAS) AF: 0.907 AC: 4382 AN: 4832

European-Finnish (FIN) AF: 0.982 AC: 10432 AN: 10620

Middle Eastern (MID) AF: 0.905 AC: 266 AN: 294

European-Non Finnish (NFE) AF: 0.942 AC: 64043 AN: 67992

Other (OTH) AF: 0.921 AC: 1947 AN: 2114

Alfa AF: 0.927 Hom.: 12036

Bravo AF: 0.902

Asia WGS AF: 0.945 AC: 3285 AN: 3476

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 12, 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	-0.74
CADD	Benign	7.3
DANN	Benign	0.45
PhyloP100		-0.25
PromoterAI		-0.017	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	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: rs6580779; hg19: chr12-51420164;