rs11568351

Variant names:

• chr2-189580468-G-C
• rs11568351
• ENST00000479598.5:n.274C>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The ENST00000479598.5(SLC40A1):​n.274C>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 1,613,064 control chromosomes in the GnomAD database, including 35,740 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2429 hom., cov: 32)
  • Exomes 𝑓: 0.21 (33311 hom.)
• Consequence: SLC40A1 ENST00000479598.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.24
• Publications: 28 publications found

Genes affected

SLC40A1 (HGNC:10909): (solute carrier family 40 member 1) The protein encoded by this gene is a cell membrane protein that may be involved in iron export from duodenal epithelial cells. Defects in this gene are a cause of hemochromatosis type 4 (HFE4). [provided by RefSeq, Jul 2008]

SLC40A1 Gene-Disease associations (from GenCC):

• hemochromatosis type 4

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.05).
• BP6: Variant 2-189580468-G-C is Benign according to our data. Variant chr2-189580468-G-C is described in ClinVar as Benign. ClinVar VariationId is 260420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.228 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC40A1	NM_014585.6	c.-8C>G		5_prime_UTR_variant	Exon 1 of 8	ENST00000261024.7	NP_055400.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC40A1	ENST00000261024.7	c.-8C>G		5_prime_UTR_variant	Exon 1 of 8	1	NM_014585.6	ENSP00000261024.3

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23827 AN: 151984 Hom.: 2429 Cov.: 32

Gnomad AFR AF: 0.0465

Gnomad AMI AF: 0.0954

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.129

Gnomad EAS AF: 0.0405

Gnomad SAS AF: 0.148

Gnomad FIN AF: 0.243

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.231

Gnomad OTH AF: 0.150

GnomAD2 exomes AF: 0.168 AC: 42131 AN: 250830 AF XY: 0.174

Gnomad AFR exome AF: 0.0405

Gnomad AMR exome AF: 0.0810

Gnomad ASJ exome AF: 0.125

Gnomad EAS exome AF: 0.0366

Gnomad FIN exome AF: 0.236

Gnomad NFE exome AF: 0.230

Gnomad OTH exome AF: 0.174

GnomAD4 exome AF: 0.206 AC: 301420 AN: 1460962 Hom.: 33311 Cov.: 35 AF XY: 0.206 AC XY: 149601 AN XY: 726830

African (AFR) AF: 0.0390 AC: 1307 AN: 33478

American (AMR) AF: 0.0861 AC: 3852 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.129 AC: 3371 AN: 26136

East Asian (EAS) AF: 0.0369 AC: 1465 AN: 39698

South Asian (SAS) AF: 0.150 AC: 12966 AN: 86256

European-Finnish (FIN) AF: 0.237 AC: 12486 AN: 52672

Middle Eastern (MID) AF: 0.158 AC: 914 AN: 5768

European-Non Finnish (NFE) AF: 0.229 AC: 254062 AN: 1111844

Other (OTH) AF: 0.182 AC: 10997 AN: 60388

GnomAD4 genome AF: 0.157 AC: 23826 AN: 152102 Hom.: 2429 Cov.: 32 AF XY: 0.155 AC XY: 11499 AN XY: 74366

African (AFR) AF: 0.0464 AC: 1927 AN: 41512

American (AMR) AF: 0.118 AC: 1802 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.129 AC: 447 AN: 3466

East Asian (EAS) AF: 0.0402 AC: 208 AN: 5172

South Asian (SAS) AF: 0.148 AC: 713 AN: 4826

European-Finnish (FIN) AF: 0.243 AC: 2561 AN: 10552

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

European-Non Finnish (NFE) AF: 0.231 AC: 15710 AN: 67968

Other (OTH) AF: 0.149 AC: 315 AN: 2112

Alfa AF: 0.199 Hom.: 1060

Bravo AF: 0.140

Asia WGS AF: 0.0960 AC: 335 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hemochromatosis type 4 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.

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	17
DANN	Benign	0.90
PhyloP100		1.2
PromoterAI		0.054	Neutral
Mutation Taster		=299/1	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: rs11568351; hg19: chr2-190445194; COSMIC: COSV53722527;