NM_014585.6:c.44-24G>C

Variant names:

• chr2-189579904-C-G
• rs1439816
• NM_014585.6:c.44-24G>C

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.44-24G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.82 in 1,612,528 control chromosomes in the GnomAD database, including 551,959 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (41236 hom., cov: 31)
  • Exomes 𝑓: 0.83 (510723 hom.)
• Consequence: SLC40A1 NM_014585.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:4
• Conservation: PhyloP100: -1.10
• Publications: 22 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=-0.8).
• BP6: Variant 2-189579904-C-G is Benign according to our data. Variant chr2-189579904-C-G is described in ClinVar as Benign. ClinVar VariationId is 1166016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.846 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC40A1	NM_014585.6	MANE Select	c.44-24G>C		intron	N/A	NP_055400.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC40A1	ENST00000261024.7	TSL:1 MANE Select	c.44-24G>C		intron	N/A	ENSP00000261024.3
	SLC40A1	ENST00000427419.5	TSL:1	c.44-24G>C		intron	N/A	ENSP00000392730.1
	SLC40A1	ENST00000440626.1	TSL:1	c.44-24G>C		intron	N/A	ENSP00000396134.1

Frequencies

GnomAD3 genomes AF: 0.705 AC: 107047 AN: 151936 Hom.: 41233 Cov.: 31

Gnomad AFR AF: 0.365

Gnomad AMI AF: 0.639

Gnomad AMR AF: 0.761

Gnomad ASJ AF: 0.819

Gnomad EAS AF: 0.837

Gnomad SAS AF: 0.747

Gnomad FIN AF: 0.881

Gnomad MID AF: 0.718

Gnomad NFE AF: 0.852

Gnomad OTH AF: 0.718

GnomAD2 exomes AF: 0.797 AC: 199818 AN: 250806 AF XY: 0.801

Gnomad AFR exome AF: 0.355

Gnomad AMR exome AF: 0.809

Gnomad ASJ exome AF: 0.810

Gnomad EAS exome AF: 0.837

Gnomad FIN exome AF: 0.876

Gnomad NFE exome AF: 0.847

Gnomad OTH exome AF: 0.794

GnomAD4 exome AF: 0.832 AC: 1215145 AN: 1460474 Hom.: 510723 Cov.: 36 AF XY: 0.830 AC XY: 603431 AN XY: 726678

African (AFR) AF: 0.335 AC: 11196 AN: 33440

American (AMR) AF: 0.803 AC: 35885 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.818 AC: 21363 AN: 26124

East Asian (EAS) AF: 0.847 AC: 33598 AN: 39688

South Asian (SAS) AF: 0.743 AC: 64080 AN: 86214

European-Finnish (FIN) AF: 0.878 AC: 46850 AN: 53378

Middle Eastern (MID) AF: 0.751 AC: 4330 AN: 5766

European-Non Finnish (NFE) AF: 0.855 AC: 949306 AN: 1110816

Other (OTH) AF: 0.804 AC: 48537 AN: 60354

GnomAD4 genome AF: 0.704 AC: 107076 AN: 152054 Hom.: 41236 Cov.: 31 AF XY: 0.707 AC XY: 52565 AN XY: 74326

African (AFR) AF: 0.364 AC: 15094 AN: 41412

American (AMR) AF: 0.761 AC: 11631 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.819 AC: 2843 AN: 3472

East Asian (EAS) AF: 0.837 AC: 4329 AN: 5170

South Asian (SAS) AF: 0.747 AC: 3595 AN: 4812

European-Finnish (FIN) AF: 0.881 AC: 9341 AN: 10602

Middle Eastern (MID) AF: 0.728 AC: 214 AN: 294

European-Non Finnish (NFE) AF: 0.852 AC: 57932 AN: 67986

Other (OTH) AF: 0.716 AC: 1514 AN: 2114

Alfa AF: 0.780 Hom.: 8577

Bravo AF: 0.683

Asia WGS AF: 0.734 AC: 2553 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hemochromatosis type 4 Uncertain:1 Benign:2

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Génetica Clinica/ Bioquímica Clínica, Genética Hospital Universitario Miguel Servet

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 18820912, 25976471)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.2
DANN	Benign	0.60
PhyloP100		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs1439816; hg19: chr2-190444630;