NM_000617.3:c.*1273G>A

Variant names:

• chr12-50987052-C-T
• rs11169654
• NM_000617.3:c.*1273G>A

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.*1273G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 1,285,696 control chromosomes in the GnomAD database, including 23,616 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1871 hom., cov: 32)
  • Exomes 𝑓: 0.19 (21745 hom.)
• Consequence: SLC11A2 NM_000617.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.40
• Publications: 12 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=-0.88).
• BP6: Variant 12-50987052-C-T is Benign according to our data. Variant chr12-50987052-C-T is described in ClinVar as Benign. ClinVar VariationId is 309287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
SLC11A2	NM_000617.3	c.*1273G>A		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.*1273G>A		3_prime_UTR_variant	Exon 16 of 16	1	NM_000617.3	ENSP00000262052.5

Frequencies

GnomAD3 genomes AF: 0.147 AC: 22389 AN: 152114 Hom.: 1866 Cov.: 32

Gnomad AFR AF: 0.0719

Gnomad AMI AF: 0.191

Gnomad AMR AF: 0.128

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.115

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.151

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.189

Gnomad OTH AF: 0.166

GnomAD2 exomes AF: 0.173 AC: 22314 AN: 129312 AF XY: 0.184

Gnomad AFR exome AF: 0.0658

Gnomad AMR exome AF: 0.113

Gnomad ASJ exome AF: 0.164

Gnomad EAS exome AF: 0.112

Gnomad FIN exome AF: 0.150

Gnomad NFE exome AF: 0.184

Gnomad OTH exome AF: 0.194

GnomAD4 exome AF: 0.192 AC: 218106 AN: 1133464 Hom.: 21745 Cov.: 36 AF XY: 0.196 AC XY: 108984 AN XY: 555920

African (AFR) AF: 0.0651 AC: 1583 AN: 24300

American (AMR) AF: 0.114 AC: 3201 AN: 28128

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 2619 AN: 15852

East Asian (EAS) AF: 0.116 AC: 1485 AN: 12832

South Asian (SAS) AF: 0.276 AC: 20891 AN: 75810

European-Finnish (FIN) AF: 0.161 AC: 2035 AN: 12604

Middle Eastern (MID) AF: 0.252 AC: 695 AN: 2754

European-Non Finnish (NFE) AF: 0.193 AC: 177613 AN: 919934

Other (OTH) AF: 0.194 AC: 7984 AN: 41250

GnomAD4 genome AF: 0.147 AC: 22397 AN: 152232 Hom.: 1871 Cov.: 32 AF XY: 0.147 AC XY: 10949 AN XY: 74430

African (AFR) AF: 0.0718 AC: 2982 AN: 41558

American (AMR) AF: 0.128 AC: 1965 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 566 AN: 3470

East Asian (EAS) AF: 0.115 AC: 594 AN: 5176

South Asian (SAS) AF: 0.265 AC: 1279 AN: 4830

European-Finnish (FIN) AF: 0.151 AC: 1603 AN: 10596

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

European-Non Finnish (NFE) AF: 0.189 AC: 12830 AN: 67992

Other (OTH) AF: 0.165 AC: 348 AN: 2112

Alfa AF: 0.176 Hom.: 2391

Bravo AF: 0.137

Asia WGS AF: 0.159 AC: 551 AN: 3478

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	-0.88
CADD	Benign	0.54
DANN	Benign	0.63
PhyloP100		-1.4
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: rs11169654; hg19: chr12-51380835;