8-22404626-C-T

Variant names:

• chr8-22404626-C-T
• rs7012503
• NM_001128431.4:c.-15-70C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001128431.4(SLC39A14):​c.-15-70C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0395 in 1,442,082 control chromosomes in the GnomAD database, including 1,258 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (106 hom., cov: 32)
  • Exomes 𝑓: 0.040 (1152 hom.)
• Consequence: SLC39A14 NM_001128431.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.190
• Publications: 1 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=-0.85).
• BP6: Variant 8-22404626-C-T is Benign according to our data. Variant chr8-22404626-C-T is described in ClinVar as Benign. ClinVar VariationId is 1222011.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0318 (4832/152120) while in subpopulation NFE AF = 0.0448 (3048/67986). AF 95% confidence interval is 0.0435. There are 106 homozygotes in GnomAd4. There are 2455 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 106 AR,AD gene

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.-15-70C>T		intron	N/A	NP_001121903.1	Q15043-1
	SLC39A14	NM_015359.6	MANE Plus Clinical	c.-15-70C>T		intron	N/A	NP_056174.2	Q15043-3
	SLC39A14	NM_001351657.2		c.16-70C>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.-15-70C>T		intron	N/A	ENSP00000352779.5	Q15043-3
	SLC39A14	ENST00000381237.6	TSL:1 MANE Select	c.-15-70C>T		intron	N/A	ENSP00000370635.1	Q15043-1
	SLC39A14	ENST00000240095.10	TSL:1	c.-15-70C>T		intron	N/A	ENSP00000240095.6	Q15043-2

Frequencies

GnomAD3 genomes AF: 0.0318 AC: 4832 AN: 152002 Hom.: 106 Cov.: 32

Gnomad AFR AF: 0.00875

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.0241

Gnomad ASJ AF: 0.0230

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0168

Gnomad FIN AF: 0.0738

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0448

Gnomad OTH AF: 0.0278

GnomAD4 exome AF: 0.0404 AC: 52067 AN: 1289962 Hom.: 1152 Cov.: 19 AF XY: 0.0399 AC XY: 25521 AN XY: 640234

African (AFR) AF: 0.00733 AC: 212 AN: 28934

American (AMR) AF: 0.0124 AC: 493 AN: 39696

Ashkenazi Jewish (ASJ) AF: 0.0226 AC: 483 AN: 21392

East Asian (EAS) AF: 0.0000518 AC: 2 AN: 38634

South Asian (SAS) AF: 0.0152 AC: 1117 AN: 73708

European-Finnish (FIN) AF: 0.0692 AC: 3354 AN: 48482

Middle Eastern (MID) AF: 0.0157 AC: 82 AN: 5216

European-Non Finnish (NFE) AF: 0.0453 AC: 44408 AN: 979738

Other (OTH) AF: 0.0354 AC: 1916 AN: 54162

GnomAD4 genome AF: 0.0318 AC: 4832 AN: 152120 Hom.: 106 Cov.: 32 AF XY: 0.0330 AC XY: 2455 AN XY: 74370

African (AFR) AF: 0.00872 AC: 362 AN: 41514

American (AMR) AF: 0.0240 AC: 367 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0230 AC: 80 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5174

South Asian (SAS) AF: 0.0168 AC: 81 AN: 4820

European-Finnish (FIN) AF: 0.0738 AC: 779 AN: 10562

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0448 AC: 3048 AN: 67986

Other (OTH) AF: 0.0275 AC: 58 AN: 2110

Alfa AF: 0.0263 Hom.: 37

Bravo AF: 0.0266

Asia WGS AF: 0.00289 AC: 10 AN: 3478

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	-0.85
CADD	Benign	3.3
DANN	Benign	0.56
PhyloP100		-0.19
PromoterAI		-0.015	Neutral
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: rs7012503; hg19: chr8-22262139;