2-189560748-T-C

Variant names:

• chr2-189560748-T-C
• rs11539983
• NM_014585.6:c.*1130A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.308
• Publications: 4 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 -20 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_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
SLC40A1	NM_014585.6	c.*1130A>G		3_prime_UTR_variant	Exon 8 of 8	ENST00000261024.7	NP_055400.1
SLC40A1	XM_047444066.1	c.*1130A>G		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.*1130A>G		3_prime_UTR_variant	Exon 8 of 8	1	NM_014585.6	ENSP00000261024.3

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00704 AC: 3 AN: 426

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2

Other (OTH) AF: 0.00 AC: 0 AN: 4

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

African (AFR) AF: 0.238 AC: 9853 AN: 41480

American (AMR) AF: 0.0513 AC: 784 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0758 AC: 263 AN: 3470

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5180

South Asian (SAS) AF: 0.0250 AC: 121 AN: 4832

European-Finnish (FIN) AF: 0.0141 AC: 150 AN: 10606

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0180 AC: 1225 AN: 68016

Other (OTH) AF: 0.0803 AC: 170 AN: 2116

Alfa AF: 0.0598 Hom.: 1244

Bravo AF: 0.0947

Asia WGS AF: 0.0220 AC: 78 AN: 3466

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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. -

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	-0.49
CADD	Benign	13
DANN	Benign	0.84
PhyloP100		0.31
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: rs11539983; hg19: chr2-190425474;