rs11568344

Positions:

• chr2-189572846-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The ENST00000261024.7(SLC40A1):​c.387C>T​(p.Leu129=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00614 in 1,600,272 control chromosomes in the GnomAD database, including 543 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (283 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (260 hom.)
• Consequence: SLC40A1 ENST00000261024.7 splice_region, synonymous
• Scores: Splicing: ADA: 0.0008543
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.269

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 2-189572846-G-A is Benign according to our data. Variant chr2-189572846-G-A is described in ClinVar as [Benign]. Clinvar id is 333170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.269 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC40A1	NM_014585.6	c.387C>T	p.Leu129=	splice_region_variant, synonymous_variant	4/8	ENST00000261024.7	NP_055400.1
SLC40A1	XM_047444066.1	c.267C>T	p.Leu89=	splice_region_variant, synonymous_variant	4/8		XP_047300022.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC40A1	ENST00000261024.7	c.387C>T	p.Leu129=	splice_region_variant, synonymous_variant	4/8	1	NM_014585.6	ENSP00000261024	P1
SLC40A1	ENST00000479598.5	n.668C>T		non_coding_transcript_exon_variant	4/4	1
SLC40A1	ENST00000427241.5	c.387C>T	p.Leu129=	splice_region_variant, synonymous_variant	6/8	5		ENSP00000390005

Frequencies

GnomAD3 genomes AF: 0.0320 AC: 4865 AN: 151900 Hom.: 282 Cov.: 32

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0128

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000471

Gnomad OTH AF: 0.0216

GnomAD3 exomes AF: 0.00858 AC: 2155 AN: 251252 Hom.: 97 AF XY: 0.00647 AC XY: 879 AN XY: 135786

Gnomad AFR exome AF: 0.117

Gnomad AMR exome AF: 0.00469

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000422

Gnomad OTH exome AF: 0.00571

GnomAD4 exome AF: 0.00342 AC: 4948 AN: 1448260 Hom.: 260 Cov.: 30 AF XY: 0.00298 AC XY: 2149 AN XY: 721336

Gnomad4 AFR exome AF: 0.120

Gnomad4 AMR exome AF: 0.00553

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000244

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000207

Gnomad4 OTH exome AF: 0.00718

GnomAD4 genome AF: 0.0321 AC: 4883 AN: 152012 Hom.: 283 Cov.: 32 AF XY: 0.0309 AC XY: 2299 AN XY: 74290

Gnomad4 AFR AF: 0.111

Gnomad4 AMR AF: 0.0128

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000471

Gnomad4 OTH AF: 0.0214

Alfa AF: 0.00664 Hom.: 120

Bravo AF: 0.0367

Asia WGS AF: 0.00520 AC: 19 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000771

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hemochromatosis type 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	10
DANN	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00085
dbscSNV1_RF	Benign	0.14
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: rs11568344; hg19: chr2-190437572;