8-22404462-G-T

Variant names:

• chr8-22404462-G-T
• rs79144383
• NM_001128431.4:c.-15-234G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001128431.4(SLC39A14):​c.-15-234G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 218,844 control chromosomes in the GnomAD database, including 7,266 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (7256 hom., cov: 22)
  • Exomes 𝑓: 0.0053 (10 hom.)
• Consequence: SLC39A14 NM_001128431.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.42
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BP6: Variant 8-22404462-G-T is Benign according to our data. Variant chr8-22404462-G-T is described in ClinVar as Benign. ClinVar VariationId is 1282183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.583 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.-15-234G>T		intron	N/A	NP_001121903.1	Q15043-1
	SLC39A14	NM_015359.6	MANE Plus Clinical	c.-15-234G>T		intron	N/A	NP_056174.2	Q15043-3
	SLC39A14	NM_001351657.2		c.16-234G>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.-15-234G>T		intron	N/A	ENSP00000352779.5	Q15043-3
	SLC39A14	ENST00000381237.6	TSL:1 MANE Select	c.-15-234G>T		intron	N/A	ENSP00000370635.1	Q15043-1
	SLC39A14	ENST00000240095.10	TSL:1	c.-15-234G>T		intron	N/A	ENSP00000240095.6	Q15043-2

Frequencies

GnomAD3 genomes AF: 0.280 AC: 36331 AN: 129674 Hom.: 7258 Cov.: 22

Gnomad AFR AF: 0.591

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.164

Gnomad SAS AF: 0.162

Gnomad FIN AF: 0.118

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.189

Gnomad OTH AF: 0.238

GnomAD4 exome AF: 0.00530 AC: 473 AN: 89188 Hom.: 10 AF XY: 0.00534 AC XY: 246 AN XY: 46084

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

African (AFR) AF: 0.0194 AC: 15 AN: 774

American (AMR) AF: 0.00528 AC: 16 AN: 3030

Ashkenazi Jewish (ASJ) AF: 0.00272 AC: 9 AN: 3312

East Asian (EAS) AF: 0.00163 AC: 11 AN: 6764

South Asian (SAS) AF: 0.0101 AC: 42 AN: 4162

European-Finnish (FIN) AF: 0.00554 AC: 32 AN: 5774

Middle Eastern (MID) AF: 0.00593 AC: 3 AN: 506

European-Non Finnish (NFE) AF: 0.00542 AC: 321 AN: 59276

Other (OTH) AF: 0.00429 AC: 24 AN: 5590

⚠️ 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: 0.280 AC: 36331 AN: 129656 Hom.: 7256 Cov.: 22 AF XY: 0.274 AC XY: 16936 AN XY: 61844

African (AFR) AF: 0.590 AC: 18995 AN: 32172

American (AMR) AF: 0.161 AC: 2071 AN: 12872

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 533 AN: 3320

East Asian (EAS) AF: 0.163 AC: 742 AN: 4556

South Asian (SAS) AF: 0.160 AC: 693 AN: 4318

European-Finnish (FIN) AF: 0.118 AC: 679 AN: 5778

Middle Eastern (MID) AF: 0.142 AC: 35 AN: 246

European-Non Finnish (NFE) AF: 0.189 AC: 12041 AN: 63762

Other (OTH) AF: 0.239 AC: 426 AN: 1784

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	1.3
DANN	Benign	0.15
PhyloP100		-2.4
PromoterAI		-0.020	Neutral
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: rs79144383; hg19: chr8-22261975; COSMIC: COSV51487167; COSMIC: COSV51487167;