rs368420430

chr2-189564177-T-Achr2-189564177-T-Cchr2-189564177-T-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PS1_Moderate BP4 BP6_Moderate BS2

The NM_014585.6(SLC40A1):c.809A>T(p.Asp270Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000521 in 1,613,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: SLC40A1 NM_014585.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter P:1 B:1
• Conservation: PhyloP100: 0.338

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 Likely_benign. Variant got -5 ACMG points.

• PS1: Transcript NM_014585.6 (SLC40A1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• BP4: Computational evidence support a benign effect (MetaRNN=0.3451803).
• BP6: Variant 2-189564177-T-A is Benign according to our data. Variant chr2-189564177-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 208987.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 34 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC40A1	NM_014585.6	c.809A>T	p.Asp270Val	missense_variant	7/8	ENST00000261024.7
SLC40A1	XM_047444066.1	c.689A>T	p.Asp230Val	missense_variant	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC40A1	ENST00000261024.7	c.809A>T	p.Asp270Val	missense_variant	7/8	1	NM_014585.6	P1

Frequencies

GnomAD3 genomes AF: 0.000224 AC: 34 AN: 152048 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000748

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: 0.0000294

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000518 AC: 13 AN: 250728 Hom.: 0 AF XY: 0.0000369 AC XY: 5 AN XY: 135526

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

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: 0.0000342 AC: 50 AN: 1461152 Hom.: 0 Cov.: 31 AF XY: 0.0000330 AC XY: 24 AN XY: 726866

Gnomad4 AFR exome AF: 0.00132

Gnomad4 AMR exome AF: 0.0000449

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.000224 AC: 34 AN: 152048 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74264

Gnomad4 AFR AF: 0.000748

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: 0.0000294

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.0000425 Hom.: 0

Bravo AF: 0.000363

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000741 AC: 9

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hemochromatosis type 4 Pathogenic:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	May 19, 2023	- -
Pathogenic, no assertion criteria provided	literature only	GeneReviews	Sep 17, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Uncertain	0.10
Cadd	Benign	14
Dann	Benign	0.97
DEOGEN2	Uncertain	0.53	D
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.088	D
MetaRNN	Benign	0.35	T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.54
Sift	Uncertain	0.013	D
Sift4G	Benign	0.16	T
Polyphen		0.0	B
Vest4		0.69
MVP		0.98
MPC		0.67
ClinPred		0.032	T
GERP RS		5.0
Varity_R		0.093
gMVP		0.55

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: rs368420430; hg19: chr2-190428903;