8-22404670-G-C

Variant names:

• chr8-22404670-G-C
• rs896377
• NM_001128431.4:c.-15-26G>C

Variant summary

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

The NM_001128431.4(SLC39A14):​c.-15-26G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.205 in 1,590,420 control chromosomes in the GnomAD database, including 38,048 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (7759 hom., cov: 31)
  • Exomes 𝑓: 0.20 (30289 hom.)
• Consequence: SLC39A14 NM_001128431.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.128

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=-0.91).
• BP6: Variant 8-22404670-G-C is Benign according to our data. Variant chr8-22404670-G-C is described in ClinVar as [Benign]. Clinvar id is 1177990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.519 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC39A14	NM_001128431.4	c.-15-26G>C		intron_variant	Intron 1 of 8	ENST00000381237.6	NP_001121903.1
SLC39A14	NM_015359.6	c.-15-26G>C		intron_variant	Intron 1 of 8	ENST00000359741.10	NP_056174.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC39A14	ENST00000359741.10	c.-15-26G>C		intron_variant	Intron 1 of 8	2	NM_015359.6	ENSP00000352779.5
SLC39A14	ENST00000381237.6	c.-15-26G>C		intron_variant	Intron 1 of 8	1	NM_001128431.4	ENSP00000370635.1

Frequencies

GnomAD3 genomes AF: 0.283 AC: 42856 AN: 151686 Hom.: 7746 Cov.: 31

Gnomad AFR AF: 0.525

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.164

Gnomad EAS AF: 0.181

Gnomad SAS AF: 0.174

Gnomad FIN AF: 0.222

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.193

Gnomad OTH AF: 0.243

GnomAD3 exomes AF: 0.203 AC: 47225 AN: 233048 Hom.: 5777 AF XY: 0.197 AC XY: 24828 AN XY: 126052

Gnomad AFR exome AF: 0.534

Gnomad AMR exome AF: 0.140

Gnomad ASJ exome AF: 0.167

Gnomad EAS exome AF: 0.189

Gnomad SAS exome AF: 0.160

Gnomad FIN exome AF: 0.219

Gnomad NFE exome AF: 0.189

Gnomad OTH exome AF: 0.183

GnomAD4 exome AF: 0.196 AC: 282415 AN: 1438618 Hom.: 30289 Cov.: 33 AF XY: 0.194 AC XY: 138410 AN XY: 712950

Gnomad4 AFR exome AF: 0.534

Gnomad4 AMR exome AF: 0.142

Gnomad4 ASJ exome AF: 0.170

Gnomad4 EAS exome AF: 0.160

Gnomad4 SAS exome AF: 0.158

Gnomad4 FIN exome AF: 0.225

Gnomad4 NFE exome AF: 0.191

Gnomad4 OTH exome AF: 0.208

GnomAD4 genome AF: 0.283 AC: 42906 AN: 151802 Hom.: 7759 Cov.: 31 AF XY: 0.279 AC XY: 20712 AN XY: 74208

Gnomad4 AFR AF: 0.525

Gnomad4 AMR AF: 0.181

Gnomad4 ASJ AF: 0.164

Gnomad4 EAS AF: 0.180

Gnomad4 SAS AF: 0.173

Gnomad4 FIN AF: 0.222

Gnomad4 NFE AF: 0.193

Gnomad4 OTH AF: 0.245

Alfa AF: 0.230 Hom.: 919

Bravo AF: 0.291

Asia WGS AF: 0.259 AC: 903 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 15, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Jul 31, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 28% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 26. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	6.9
DANN	Benign	0.52

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: rs896377; hg19: chr8-22262183; COSMIC: COSV51484321;