2-189561589-C-A

Variant names:

• chr2-189561589-C-A
• rs61525883
• NM_014585.6:c.*289G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_014585.6(SLC40A1):​c.*289G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00717 in 360,572 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.014 (59 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (12 hom.)
• Consequence: SLC40A1 NM_014585.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.588
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-189561589-C-A is Benign according to our data. Variant chr2-189561589-C-A is described in ClinVar as [Benign]. Clinvar id is 333159.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0142 (2161/152206) while in subpopulation AFR AF = 0.05 (2077/41504). AF 95% confidence interval is 0.0483. There are 59 homozygotes in GnomAd4. There are 1008 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 59 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC40A1	NM_014585.6	c.*289G>T		3_prime_UTR_variant	Exon 8 of 8	ENST00000261024.7	NP_055400.1
SLC40A1	XM_047444066.1	c.*289G>T		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.*289G>T		3_prime_UTR_variant	Exon 8 of 8	1	NM_014585.6	ENSP00000261024.3

Frequencies

GnomAD3 genomes AF: 0.0142 AC: 2154 AN: 152088 Hom.: 58 Cov.: 33

Gnomad AFR AF: 0.0500

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.0110

GnomAD4 exome AF: 0.00204 AC: 426 AN: 208366 Hom.: 12 Cov.: 0 AF XY: 0.00175 AC XY: 193 AN XY: 110368

African (AFR) AF: 0.0525 AC: 346 AN: 6590

American (AMR) AF: 0.00264 AC: 20 AN: 7572

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6402

East Asian (EAS) AF: 0.0000816 AC: 1 AN: 12256

South Asian (SAS) AF: 0.000227 AC: 6 AN: 26414

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9600

Middle Eastern (MID) AF: 0.00109 AC: 1 AN: 920

European-Non Finnish (NFE) AF: 0.0000947 AC: 12 AN: 126758

Other (OTH) AF: 0.00337 AC: 40 AN: 11854

GnomAD4 genome AF: 0.0142 AC: 2161 AN: 152206 Hom.: 59 Cov.: 33 AF XY: 0.0135 AC XY: 1008 AN XY: 74418

African (AFR) AF: 0.0500 AC: 2077 AN: 41504

American (AMR) AF: 0.00333 AC: 51 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68016

Other (OTH) AF: 0.0109 AC: 23 AN: 2114

Alfa AF: 0.00347 Hom.: 2

Bravo AF: 0.0160

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hemochromatosis type 4 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	-0.85
CADD	Benign	0.12
DANN	Benign	0.53
PhyloP100		-0.59
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: rs61525883; hg19: chr2-190426315;