8-22404585-A-G

Position:

• chr8-22404585-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000381237.6(SLC39A14):​c.-15-111A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.496 in 994,824 control chromosomes in the GnomAD database, including 126,781 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (25779 hom., cov: 30)
  • Exomes 𝑓: 0.48 (101002 hom.)
• Consequence: SLC39A14 ENST00000381237.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0730

Genes affected

SLC39A14 (HGNC:20858): (solute carrier family 39 member 14) This gene encodes a member of the the SLC39A family of divalent metal transporters that mediates the cellular uptake of manganese, zinc, iron, and cadmium. The encoded protein contains eight transmembrane domains, a histidine-rich motif, and a metalloprotease motif, and is expressed on the plasma membrane and the endocytic vesicle membrane. It is an important transporter of nontransferrin-bound iron and a critical regulator of manganese homeostasis. Naturally occurring mutations in this gene are associated with neurodegeneration with brain iron accumulation and early-onset parkinsonism-dystonia with hypermanganesemia. [provided by RefSeq, May 2017]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 8-22404585-A-G is Benign according to our data. Variant chr8-22404585-A-G is described in ClinVar as [Benign]. Clinvar id is 1246155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.751 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC39A14	NM_001128431.4	c.-15-111A>G		intron_variant		ENST00000381237.6	NP_001121903.1
SLC39A14	NM_015359.6	c.-15-111A>G		intron_variant		ENST00000359741.10	NP_056174.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC39A14	ENST00000359741.10	c.-15-111A>G		intron_variant		2	NM_015359.6	ENSP00000352779	A2
SLC39A14	ENST00000381237.6	c.-15-111A>G		intron_variant		1	NM_001128431.4	ENSP00000370635	P4

Frequencies

GnomAD3 genomes AF: 0.570 AC: 86417 AN: 151632 Hom.: 25749 Cov.: 30

Gnomad AFR AF: 0.758

Gnomad AMI AF: 0.532

Gnomad AMR AF: 0.513

Gnomad ASJ AF: 0.486

Gnomad EAS AF: 0.694

Gnomad SAS AF: 0.549

Gnomad FIN AF: 0.533

Gnomad MID AF: 0.494

Gnomad NFE AF: 0.472

Gnomad OTH AF: 0.533

GnomAD4 exome AF: 0.483 AC: 407163 AN: 843074 Hom.: 101002 Cov.: 11 AF XY: 0.484 AC XY: 207670 AN XY: 429502

Gnomad4 AFR exome AF: 0.751

Gnomad4 AMR exome AF: 0.501

Gnomad4 ASJ exome AF: 0.491

Gnomad4 EAS exome AF: 0.680

Gnomad4 SAS exome AF: 0.529

Gnomad4 FIN exome AF: 0.540

Gnomad4 NFE exome AF: 0.452

Gnomad4 OTH exome AF: 0.496

GnomAD4 genome AF: 0.570 AC: 86498 AN: 151750 Hom.: 25779 Cov.: 30 AF XY: 0.570 AC XY: 42293 AN XY: 74144

Gnomad4 AFR AF: 0.759

Gnomad4 AMR AF: 0.512

Gnomad4 ASJ AF: 0.486

Gnomad4 EAS AF: 0.694

Gnomad4 SAS AF: 0.548

Gnomad4 FIN AF: 0.533

Gnomad4 NFE AF: 0.472

Gnomad4 OTH AF: 0.534

Alfa AF: 0.530 Hom.: 2813

Bravo AF: 0.575

Asia WGS AF: 0.644 AC: 2238 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 15, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	3.6
DANN	Benign	0.51

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: rs896375; hg19: chr8-22262098; COSMIC: COSV51483513;