rs11568350

Variant names:

• chr2-189565370-C-A
• rs11568350
• NM_014585.6:c.744G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-189565370-C-A
• chr2-189565370-C-G
• chr2-189565370-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014585.6(SLC40A1):​c.744G>T​(p.Gln248His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00267 in 1,614,214 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q248L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.015 (52 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (48 hom.)
• Consequence: SLC40A1 NM_014585.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.232
• Publications: 51 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0053548813).
• BP6: Variant 2-189565370-C-A is Benign according to our data. Variant chr2-189565370-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 333167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0146 (2227/152346) while in subpopulation AFR AF = 0.0507 (2108/41582). AF 95% confidence interval is 0.0489. There are 52 homozygotes in GnomAd4. There are 1019 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 52 AR,AD 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.744G>T	p.Gln248His	missense	Exon 6 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.744G>T	p.Gln248His	missense	Exon 6 of 8	ENSP00000261024.3	Q9NP59
	SLC40A1	ENST00000852923.1		c.744G>T	p.Gln248His	missense	Exon 8 of 10	ENSP00000522982.1
	SLC40A1	ENST00000852924.1		c.744G>T	p.Gln248His	missense	Exon 7 of 9	ENSP00000522983.1

Frequencies

GnomAD3 genomes AF: 0.0146 AC: 2217 AN: 152228 Hom.: 52 Cov.: 32

Gnomad AFR AF: 0.0506

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00563

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: 0.000132

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00378 AC: 951 AN: 251364 AF XY: 0.00249

Gnomad AFR exome AF: 0.0528

Gnomad AMR exome AF: 0.00194

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: 0.00130

GnomAD4 exome AF: 0.00143 AC: 2089 AN: 1461868 Hom.: 48 Cov.: 31 AF XY: 0.00116 AC XY: 844 AN XY: 727236

African (AFR) AF: 0.0514 AC: 1721 AN: 33476

American (AMR) AF: 0.00239 AC: 107 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.0000387 AC: 43 AN: 1112002

Other (OTH) AF: 0.00336 AC: 203 AN: 60392

GnomAD4 genome AF: 0.0146 AC: 2227 AN: 152346 Hom.: 52 Cov.: 32 AF XY: 0.0137 AC XY: 1019 AN XY: 74492

African (AFR) AF: 0.0507 AC: 2108 AN: 41582

American (AMR) AF: 0.00562 AC: 86 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68030

Other (OTH) AF: 0.0113 AC: 24 AN: 2116

Alfa AF: 0.00576 Hom.: 50

Bravo AF: 0.0168

ESP6500AA AF: 0.0581 AC: 256

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00468 AC: 568

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely 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
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Uncertain	0.57	D
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.23
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.34
Sift	Benign	0.13	T
Sift4G	Benign	0.22	T
Polyphen		0.010	B
Vest4		0.098
MutPred		0.067		Loss of helix (P = 0.2022)
MVP		0.50
MPC		0.45
ClinPred		0.0097	T
GERP RS		0.59
Varity_R		0.096
gMVP		0.63
Mutation Taster		=91/9	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: rs11568350; hg19: chr2-190430096; COSMIC: COSV99038676; COSMIC: COSV99038676;