2-189561934-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_014585.6(SLC40A1):c.1660G>A(p.Gly554Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,916 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: SLC40A1 NM_014585.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.27

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06706825).
• BS2: High AC in GnomAd at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC40A1	NM_014585.6	c.1660G>A	p.Gly554Ser	missense_variant	8/8	ENST00000261024.7
SLC40A1	XM_047444066.1	c.1540G>A	p.Gly514Ser	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC40A1	ENST00000261024.7	c.1660G>A	p.Gly554Ser	missense_variant	8/8	1	NM_014585.6	P1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152096 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251312 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135820

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000150 AC: 22 AN: 1461820 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 727204

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152096 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74286

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000162 Hom.: 0

Bravo AF: 0.0000416

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 07, 2022

The c.1660G>A (p.G554S) alteration is located in exon 8 (coding exon 8) of the SLC40A1 gene. This alteration results from a G to A substitution at nucleotide position 1660, causing the glycine (G) at amino acid position 554 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Hemochromatosis type 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 30, 2021

This sequence change replaces glycine with serine at codon 554 of the SLC40A1 protein (p.Gly554Ser). The glycine residue is weakly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs369255146, ExAC 0.02%). This variant has not been reported in the literature in individuals affected with SLC40A1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	5.1
Dann	Benign	0.42
DEOGEN2	Benign	0.14	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.93
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	0.98	N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.91	N
REVEL	Benign	0.22
Sift	Benign	0.67	T
Sift4G	Benign	1.0	T
Polyphen		0.10	B
Vest4		0.035
MVP		0.21
MPC		0.50
ClinPred		0.016	T
GERP RS		0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.020
gMVP		0.20

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: rs369255146; hg19: chr2-190426660;