rs201805867

Variant names:

• chr2-189561828-C-T
• rs201805867
• NM_014585.6:c.*50G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_014585.6(SLC40A1):​c.*50G>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 0.000722 in 1,471,416 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00073 (1 hom.)
• Consequence: SLC40A1 NM_014585.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.968
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC40A1	NM_014585.6	c.*50G>A		3_prime_UTR_variant	Exon 8 of 8	ENST00000261024.7	NP_055400.1
SLC40A1	XM_047444066.1	c.*50G>A		3_prime_UTR_variant	Exon 8 of 8		XP_047300022.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC40A1	ENST00000261024.7	c.*50G>A		3_prime_UTR_variant	Exon 8 of 8	1	NM_014585.6	ENSP00000261024.3

Frequencies

GnomAD3 genomes AF: 0.000657 AC: 100 AN: 152148 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00122

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000577 AC: 142 AN: 246176 AF XY: 0.000586

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000555

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000286

Gnomad NFE exome AF: 0.000796

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.000729 AC: 962 AN: 1319150 Hom.: 1 Cov.: 19 AF XY: 0.000726 AC XY: 482 AN XY: 664238

African (AFR) AF: 0.0000978 AC: 3 AN: 30660

American (AMR) AF: 0.000564 AC: 25 AN: 44300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25204

East Asian (EAS) AF: 0.0000257 AC: 1 AN: 38968

South Asian (SAS) AF: 0.000591 AC: 49 AN: 82858

European-Finnish (FIN) AF: 0.000323 AC: 17 AN: 52634

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5504

European-Non Finnish (NFE) AF: 0.000855 AC: 841 AN: 983304

Other (OTH) AF: 0.000467 AC: 26 AN: 55718

GnomAD4 genome AF: 0.000657 AC: 100 AN: 152266 Hom.: 0 Cov.: 33 AF XY: 0.000645 AC XY: 48 AN XY: 74444

African (AFR) AF: 0.000168 AC: 7 AN: 41546

American (AMR) AF: 0.000262 AC: 4 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00122 AC: 83 AN: 68018

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000861 Hom.: 0

Bravo AF: 0.000574

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	16
DANN	Benign	0.81
PhyloP100		0.97
Mutation Taster		=100/0	polymorphism

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: rs201805867; hg19: chr2-190426554;