rs11568345

Variant names:

• chr2-189572906-G-A
• rs11568345
• NM_014585.6:c.327C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-189572906-G-A
• chr2-189572906-G-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_014585.6(SLC40A1):​c.327C>T​(p.Ile109Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00415 in 1,613,972 control chromosomes in the GnomAD database, including 254 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. I109I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.023 (133 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (121 hom.)
• Consequence: SLC40A1 NM_014585.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.510
• Publications: 2 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 2-189572906-G-A is Benign according to our data. Variant chr2-189572906-G-A is described in ClinVar as Benign. ClinVar VariationId is 333171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.51 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0771 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.327C>T	p.Ile109Ile	synonymous	Exon 4 of 8	NP_055400.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC40A1	ENST00000261024.7	TSL:1 MANE Select	c.327C>T	p.Ile109Ile	synonymous	Exon 4 of 8	ENSP00000261024.3
	SLC40A1	ENST00000479598.5	TSL:1	n.608C>T		non_coding_transcript_exon	Exon 4 of 4
	SLC40A1	ENST00000427241.5	TSL:5	c.327C>T	p.Ile109Ile	synonymous	Exon 6 of 8	ENSP00000390005.1

Frequencies

GnomAD3 genomes AF: 0.0228 AC: 3474 AN: 152142 Hom.: 133 Cov.: 32

Gnomad AFR AF: 0.0795

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00864

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.00596 AC: 1499 AN: 251378 AF XY: 0.00439

Gnomad AFR exome AF: 0.0831

Gnomad AMR exome AF: 0.00341

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00220 AC: 3222 AN: 1461712 Hom.: 121 Cov.: 31 AF XY: 0.00187 AC XY: 1360 AN XY: 727160

African (AFR) AF: 0.0797 AC: 2667 AN: 33468

American (AMR) AF: 0.00434 AC: 194 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.0000522 AC: 58 AN: 1111882

Other (OTH) AF: 0.00459 AC: 277 AN: 60392

GnomAD4 genome AF: 0.0229 AC: 3480 AN: 152260 Hom.: 133 Cov.: 32 AF XY: 0.0217 AC XY: 1619 AN XY: 74462

African (AFR) AF: 0.0794 AC: 3297 AN: 41524

American (AMR) AF: 0.00863 AC: 132 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68028

Other (OTH) AF: 0.0170 AC: 36 AN: 2116

Alfa AF: 0.00793 Hom.: 81

Bravo AF: 0.0272

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hemochromatosis type 4 (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	9.0
DANN	Benign	0.77
PhyloP100		0.51
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: rs11568345; hg19: chr2-190437632;