2-189560748-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_014585.6(SLC40A1):c.*1130A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0828 in 152,620 control chromosomes in the GnomAD database, including 1,298 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.083 (1298 hom., cov: 33)
  • Exomes 𝑓: 0.0069 (0 hom.)
• Consequence: SLC40A1 NM_014585.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.308

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 2-189560748-T-C is Benign according to our data. Variant chr2-189560748-T-C is described in ClinVar as [Benign]. Clinvar id is 333153.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.234 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC40A1	NM_014585.6	c.*1130A>G		3_prime_UTR_variant	8/8	ENST00000261024.7
SLC40A1	XM_047444066.1	c.*1130A>G		3_prime_UTR_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC40A1	ENST00000261024.7	c.*1130A>G		3_prime_UTR_variant	8/8	1	NM_014585.6	P1

Frequencies

GnomAD3 genomes AF: 0.0829 AC: 12600 AN: 152070 Hom.: 1296 Cov.: 33

Gnomad AFR AF: 0.237

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.0514

Gnomad ASJ AF: 0.0758

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0254

Gnomad FIN AF: 0.0141

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0180

Gnomad OTH AF: 0.0817

GnomAD4 exome AF: 0.00694 AC: 3 AN: 432 Hom.: 0 Cov.: 0 AF XY: 0.00385 AC XY: 1 AN XY: 260

Gnomad4 FIN exome AF: 0.00704

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0830 AC: 12631 AN: 152188 Hom.: 1298 Cov.: 33 AF XY: 0.0804 AC XY: 5980 AN XY: 74424

Gnomad4 AFR AF: 0.238

Gnomad4 AMR AF: 0.0513

Gnomad4 ASJ AF: 0.0758

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0250

Gnomad4 FIN AF: 0.0141

Gnomad4 NFE AF: 0.0180

Gnomad4 OTH AF: 0.0803

Alfa AF: 0.0376 Hom.: 326

Bravo AF: 0.0947

Asia WGS AF: 0.0220 AC: 78 AN: 3466

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hemochromatosis type 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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	-0.49
Cadd	Benign	13
Dann	Benign	0.84

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

Publications

LitVar

Other links and lift over

dbSNP: rs11539983; hg19: chr2-190425474;