2-189579666-T-C

Variant names:

• chr2-189579666-T-C
• rs1123109
• NM_014585.6:c.111+147A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014585.6(SLC40A1):​c.111+147A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 742,714 control chromosomes in the GnomAD database, including 14,902 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 0.16 (2424 hom., cov: 33)
  • Exomes 𝑓: 0.19 (12478 hom.)
• Consequence: SLC40A1 NM_014585.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0700
• Publications: 19 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: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia, G2P, Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.227 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014585.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC40A1	NM_014585.6	MANE Select	c.111+147A>G		intron	N/A	NP_055400.1	Q9NP59

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC40A1	ENST00000261024.7	TSL:1 MANE Select	c.111+147A>G		intron	N/A	ENSP00000261024.3	Q9NP59
	SLC40A1	ENST00000479598.5	TSL:1	n.392+147A>G		intron	N/A
	SLC40A1	ENST00000852923.1		c.111+147A>G		intron	N/A	ENSP00000522982.1

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23823 AN: 152128 Hom.: 2423 Cov.: 33

Gnomad AFR AF: 0.0469

Gnomad AMI AF: 0.0954

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.129

Gnomad EAS AF: 0.0494

Gnomad SAS AF: 0.149

Gnomad FIN AF: 0.243

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.230

Gnomad OTH AF: 0.152

GnomAD4 exome AF: 0.195 AC: 114889 AN: 590468 Hom.: 12478 AF XY: 0.195 AC XY: 61822 AN XY: 317518

African (AFR) AF: 0.0447 AC: 717 AN: 16054

American (AMR) AF: 0.0896 AC: 3063 AN: 34202

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 2561 AN: 19572

East Asian (EAS) AF: 0.0472 AC: 1517 AN: 32114

South Asian (SAS) AF: 0.152 AC: 9563 AN: 62936

European-Finnish (FIN) AF: 0.235 AC: 11480 AN: 48790

Middle Eastern (MID) AF: 0.157 AC: 558 AN: 3562

European-Non Finnish (NFE) AF: 0.233 AC: 79778 AN: 342118

Other (OTH) AF: 0.182 AC: 5652 AN: 31120

GnomAD4 genome AF: 0.156 AC: 23823 AN: 152246 Hom.: 2424 Cov.: 33 AF XY: 0.154 AC XY: 11486 AN XY: 74418

African (AFR) AF: 0.0468 AC: 1945 AN: 41566

American (AMR) AF: 0.118 AC: 1804 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.129 AC: 448 AN: 3472

East Asian (EAS) AF: 0.0492 AC: 255 AN: 5188

South Asian (SAS) AF: 0.149 AC: 718 AN: 4832

European-Finnish (FIN) AF: 0.243 AC: 2567 AN: 10580

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.230 AC: 15625 AN: 67998

Other (OTH) AF: 0.151 AC: 319 AN: 2108

Alfa AF: 0.196 Hom.: 5873

Bravo AF: 0.140

Asia WGS AF: 0.102 AC: 356 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.2
DANN	Benign	0.26
PhyloP100		-0.070
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: rs1123109; hg19: chr2-190444392;