chr8-22376123-G-T

Variant names:

• chr8-22376123-G-T
• rs4872479
• NM_001128431.4:c.-16+8715G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001128431.4(SLC39A14):​c.-16+8715G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 152,030 control chromosomes in the GnomAD database, including 1,632 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.11 (1632 hom., cov: 32)
• Consequence: SLC39A14 NM_001128431.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.821
• Publications: 5 publications found

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]

SLC39A14 Gene-Disease associations (from GenCC):

• hypermanganesemia with dystonia 2

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• hyperostosis cranialis interna

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.255 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128431.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC39A14	NM_001128431.4	MANE Select	c.-16+8715G>T		intron	N/A	NP_001121903.1	Q15043-1
	SLC39A14	NM_015359.6	MANE Plus Clinical	c.-16+8715G>T		intron	N/A	NP_056174.2	Q15043-3
	SLC39A14	NM_001351657.2		c.-283+8715G>T		intron	N/A	NP_001338586.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC39A14	ENST00000359741.10	TSL:2 MANE Plus Clinical	c.-16+8715G>T		intron	N/A	ENSP00000352779.5	Q15043-3
	SLC39A14	ENST00000381237.6	TSL:1 MANE Select	c.-16+8715G>T		intron	N/A	ENSP00000370635.1	Q15043-1
	SLC39A14	ENST00000240095.10	TSL:1	c.-16+8715G>T		intron	N/A	ENSP00000240095.6	Q15043-2

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16796 AN: 151912 Hom.: 1627 Cov.: 32

Gnomad AFR AF: 0.259

Gnomad AMI AF: 0.0800

Gnomad AMR AF: 0.0652

Gnomad ASJ AF: 0.0384

Gnomad EAS AF: 0.0903

Gnomad SAS AF: 0.0470

Gnomad FIN AF: 0.0906

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0451

Gnomad OTH AF: 0.0857

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.111 AC: 16828 AN: 152030 Hom.: 1632 Cov.: 32 AF XY: 0.111 AC XY: 8223 AN XY: 74348

African (AFR) AF: 0.259 AC: 10716 AN: 41412

American (AMR) AF: 0.0653 AC: 998 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0384 AC: 133 AN: 3468

East Asian (EAS) AF: 0.0901 AC: 466 AN: 5170

South Asian (SAS) AF: 0.0471 AC: 227 AN: 4824

European-Finnish (FIN) AF: 0.0906 AC: 957 AN: 10562

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0450 AC: 3063 AN: 68004

Other (OTH) AF: 0.0891 AC: 188 AN: 2110

Alfa AF: 0.0743 Hom.: 1188

Bravo AF: 0.118

Asia WGS AF: 0.106 AC: 369 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.30
DANN	Benign	0.37
PhyloP100		-0.82
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4872479; hg19: chr8-22233636;