8-22404462-GTTTTT-GTTTTTT

Variant names:

• chr8-22404462-G-GT
• rs61222646
• NM_001128431.4:c.-15-221dupT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_001128431.4(SLC39A14):​c.-15-221dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.017 in 219,958 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 20)
  • Exomes 𝑓: 0.040 (0 hom.)
• Consequence: SLC39A14 NM_001128431.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.139
• Publications: 0 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: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)
• hyperostosis cranialis interna

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0015 (198/131666) while in subpopulation AFR AF = 0.00313 (103/32884). AF 95% confidence interval is 0.00264. There are 1 homozygotes in GnomAd4. There are 103 alleles in the male GnomAd4 subpopulation. Median coverage is 20. This position passed quality control check.

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.-15-221dupT		intron	N/A	NP_001121903.1	Q15043-1
	SLC39A14	NM_015359.6	MANE Plus Clinical	c.-15-221dupT		intron	N/A	NP_056174.2	Q15043-3
	SLC39A14	NM_001351657.2		c.16-221dupT		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.-15-234_-15-233insT		intron	N/A	ENSP00000352779.5	Q15043-3
	SLC39A14	ENST00000381237.6	TSL:1 MANE Select	c.-15-234_-15-233insT		intron	N/A	ENSP00000370635.1	Q15043-1
	SLC39A14	ENST00000240095.10	TSL:1	c.-15-234_-15-233insT		intron	N/A	ENSP00000240095.6	Q15043-2

Frequencies

GnomAD3 genomes AF: 0.00150 AC: 198 AN: 131686 Hom.: 1 Cov.: 20

Gnomad AFR AF: 0.00314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000533

Gnomad ASJ AF: 0.000898

Gnomad EAS AF: 0.00299

Gnomad SAS AF: 0.00158

Gnomad FIN AF: 0.000831

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000887

Gnomad OTH AF: 0.00110

GnomAD4 exome AF: 0.0402 AC: 3552 AN: 88292 Hom.: 0 AF XY: 0.0402 AC XY: 1831 AN XY: 45584

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0749 AC: 58 AN: 774

American (AMR) AF: 0.0392 AC: 118 AN: 3012

Ashkenazi Jewish (ASJ) AF: 0.0358 AC: 117 AN: 3270

East Asian (EAS) AF: 0.0186 AC: 125 AN: 6714

South Asian (SAS) AF: 0.0304 AC: 126 AN: 4138

European-Finnish (FIN) AF: 0.0297 AC: 171 AN: 5752

Middle Eastern (MID) AF: 0.0587 AC: 29 AN: 494

European-Non Finnish (NFE) AF: 0.0439 AC: 2570 AN: 58590

Other (OTH) AF: 0.0429 AC: 238 AN: 5548

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00150 AC: 198 AN: 131666 Hom.: 1 Cov.: 20 AF XY: 0.00164 AC XY: 103 AN XY: 62906

African (AFR) AF: 0.00313 AC: 103 AN: 32884

American (AMR) AF: 0.000532 AC: 7 AN: 13148

Ashkenazi Jewish (ASJ) AF: 0.000898 AC: 3 AN: 3340

East Asian (EAS) AF: 0.00300 AC: 14 AN: 4664

South Asian (SAS) AF: 0.00159 AC: 7 AN: 4400

European-Finnish (FIN) AF: 0.000831 AC: 5 AN: 6020

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 264

European-Non Finnish (NFE) AF: 0.000887 AC: 57 AN: 64272

Other (OTH) AF: 0.00110 AC: 2 AN: 1820

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.14
Mutation Taster		=100/0	polymorphism

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: rs61222646; hg19: chr8-22261975;