2-189580016-T-C

Variant names:

• chr2-189580016-T-C
• rs13431938
• NM_014585.6:c.44-136A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_014585.6(SLC40A1):​c.44-136A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000811 in 876,806 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (2 hom.)
• Consequence: SLC40A1 NM_014585.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.05
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00303 (462/152362) while in subpopulation AFR AF = 0.0107 (446/41578). AF 95% confidence interval is 0.00991. There are 1 homozygotes in GnomAd4. There are 222 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

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.44-136A>G		intron	N/A	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.44-136A>G		intron	N/A	ENSP00000261024.3	Q9NP59
	SLC40A1	ENST00000427419.5	TSL:1	c.44-136A>G		intron	N/A	ENSP00000392730.1	Q4PNE6
	SLC40A1	ENST00000440626.1	TSL:1	c.44-136A>G		intron	N/A	ENSP00000396134.1	Q4PNE6

Frequencies

GnomAD3 genomes AF: 0.00303 AC: 461 AN: 152244 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0107

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000719

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00191

GnomAD4 exome AF: 0.000344 AC: 249 AN: 724444 Hom.: 2 AF XY: 0.000276 AC XY: 105 AN XY: 380798

African (AFR) AF: 0.0110 AC: 200 AN: 18194

American (AMR) AF: 0.000376 AC: 13 AN: 34542

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20848

East Asian (EAS) AF: 0.0000305 AC: 1 AN: 32774

South Asian (SAS) AF: 0.0000458 AC: 3 AN: 65522

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47580

Middle Eastern (MID) AF: 0.000229 AC: 1 AN: 4364

European-Non Finnish (NFE) AF: 0.0000108 AC: 5 AN: 464824

Other (OTH) AF: 0.000726 AC: 26 AN: 35796

GnomAD4 genome AF: 0.00303 AC: 462 AN: 152362 Hom.: 1 Cov.: 32 AF XY: 0.00298 AC XY: 222 AN XY: 74504

African (AFR) AF: 0.0107 AC: 446 AN: 41578

American (AMR) AF: 0.000718 AC: 11 AN: 15310

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00227 Hom.: 0

Bravo AF: 0.00318

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.57
DANN	Benign	0.59
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism

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: rs13431938; hg19: chr2-190444742;