rs11568350

chr2-189565370-C-Achr2-189565370-C-T

Variant summary

Our verdict is Benign. Variant got -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. 13/19 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:2
• Conservation: PhyloP100: 0.232

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 -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 2217 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC40A1	NM_014585.6	c.744G>T	p.Gln248His	missense_variant	6/8	ENST00000261024.7
SLC40A1	XM_047444066.1	c.624G>T	p.Gln208His	missense_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC40A1	ENST00000261024.7	c.744G>T	p.Gln248His	missense_variant	6/8	1	NM_014585.6	P1

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

GnomAD3 exomes AF: 0.00378 AC: 951 AN: 251364 Hom.: 26 AF XY: 0.00249 AC XY: 338 AN XY: 135876

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 SAS exome AF: 0.000196

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

Gnomad4 AFR exome AF: 0.0514

Gnomad4 AMR exome AF: 0.00239

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000387

Gnomad4 OTH exome AF: 0.00336

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

Gnomad4 AFR AF: 0.0507

Gnomad4 AMR AF: 0.00562

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.0113

Alfa AF: 0.00302 Hom.: 16

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

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hemochromatosis type 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 13, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	D
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs11568350; hg19: chr2-190430096; COSMIC: COSV99038676; COSMIC: COSV99038676;