rs11568344

Variant names:

• chr2-189572846-G-A
• rs11568344
• NM_014585.6:c.387C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-189572846-G-A
• chr2-189572846-G-C

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.387C>T​(p.Leu129Leu) 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 NM_014585.6 splice_region, synonymous
• Scores: Splicing: ADA: 0.0008543
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.269
• Publications: 8 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 -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 VariationId 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.

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.387C>T	p.Leu129Leu	splice_region synonymous	Exon 4 of 8	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.387C>T	p.Leu129Leu	splice_region synonymous	Exon 4 of 8	ENSP00000261024.3	Q9NP59
	SLC40A1	ENST00000479598.5	TSL:1	n.668C>T		non_coding_transcript_exon	Exon 4 of 4
	SLC40A1	ENST00000852923.1		c.387C>T	p.Leu129Leu	splice_region synonymous	Exon 6 of 10	ENSP00000522982.1

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

GnomAD2 exomes AF: 0.00858 AC: 2155 AN: 251252 AF XY: 0.00647

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 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

African (AFR) AF: 0.120 AC: 3971 AN: 33076

American (AMR) AF: 0.00553 AC: 247 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26030

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39624

South Asian (SAS) AF: 0.000244 AC: 21 AN: 86006

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00869 AC: 50 AN: 5754

European-Non Finnish (NFE) AF: 0.000207 AC: 228 AN: 1099788

Other (OTH) AF: 0.00718 AC: 430 AN: 59888

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

African (AFR) AF: 0.111 AC: 4606 AN: 41454

American (AMR) AF: 0.0128 AC: 195 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10540

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000471 AC: 32 AN: 67984

Other (OTH) AF: 0.0214 AC: 45 AN: 2106

Alfa AF: 0.0125 Hom.: 336

Bravo AF: 0.0367

Asia WGS AF: 0.00520 AC: 19 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000771

ClinVar

ClinVar submissions

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	-0.38
CADD	Benign	10
DANN	Benign	0.75
PhyloP100		0.27
Mutation Taster		=66/34	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00085
dbscSNV1_RF	Benign	0.14
Splicevardb		1.0
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: rs11568344; hg19: chr2-190437572;