rs2304704

Positions:

• chr2-189565451-A-G
• chr2-189565451-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014585.6(SLC40A1):​c.663T>C​(p.Val221=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.617 in 1,613,956 control chromosomes in the GnomAD database, including 314,691 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (23598 hom., cov: 33)
  • Exomes 𝑓: 0.63 (291093 hom.)
• Consequence: SLC40A1 NM_014585.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.422

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 2-189565451-A-G is Benign according to our data. Variant chr2-189565451-A-G is described in ClinVar as [Benign]. Clinvar id is 260422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-189565451-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.422 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.781 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC40A1	NM_014585.6	c.663T>C	p.Val221=	synonymous_variant	6/8	ENST00000261024.7	NP_055400.1
SLC40A1	XM_047444066.1	c.543T>C	p.Val181=	synonymous_variant	6/8		XP_047300022.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC40A1	ENST00000261024.7	c.663T>C	p.Val221=	synonymous_variant	6/8	1	NM_014585.6	ENSP00000261024	P1

Frequencies

GnomAD3 genomes AF: 0.524 AC: 79693 AN: 152002 Hom.: 23605 Cov.: 33

Gnomad AFR AF: 0.228

Gnomad AMI AF: 0.805

Gnomad AMR AF: 0.666

Gnomad ASJ AF: 0.714

Gnomad EAS AF: 0.802

Gnomad SAS AF: 0.633

Gnomad FIN AF: 0.569

Gnomad MID AF: 0.625

Gnomad NFE AF: 0.621

Gnomad OTH AF: 0.575

GnomAD3 exomes AF: 0.629 AC: 158018 AN: 251364 Hom.: 51703 AF XY: 0.632 AC XY: 85840 AN XY: 135854

Gnomad AFR exome AF: 0.214

Gnomad AMR exome AF: 0.747

Gnomad ASJ exome AF: 0.719

Gnomad EAS exome AF: 0.792

Gnomad SAS exome AF: 0.638

Gnomad FIN exome AF: 0.570

Gnomad NFE exome AF: 0.625

Gnomad OTH exome AF: 0.646

GnomAD4 exome AF: 0.626 AC: 915351 AN: 1461834 Hom.: 291093 Cov.: 60 AF XY: 0.627 AC XY: 456034 AN XY: 727220

Gnomad4 AFR exome AF: 0.213

Gnomad4 AMR exome AF: 0.736

Gnomad4 ASJ exome AF: 0.720

Gnomad4 EAS exome AF: 0.802

Gnomad4 SAS exome AF: 0.634

Gnomad4 FIN exome AF: 0.570

Gnomad4 NFE exome AF: 0.628

Gnomad4 OTH exome AF: 0.626

GnomAD4 genome AF: 0.524 AC: 79672 AN: 152122 Hom.: 23598 Cov.: 33 AF XY: 0.529 AC XY: 39329 AN XY: 74358

Gnomad4 AFR AF: 0.228

Gnomad4 AMR AF: 0.666

Gnomad4 ASJ AF: 0.714

Gnomad4 EAS AF: 0.801

Gnomad4 SAS AF: 0.632

Gnomad4 FIN AF: 0.569

Gnomad4 NFE AF: 0.621

Gnomad4 OTH AF: 0.572

Alfa AF: 0.594 Hom.: 25005

Bravo AF: 0.522

Asia WGS AF: 0.674 AC: 2343 AN: 3478

EpiCase AF: 0.638

EpiControl AF: 0.635

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Hemochromatosis type 4 Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	7.7
DANN	Benign	0.76

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: rs2304704; hg19: chr2-190430177;