chr8-22404541-A-G

Variant names:

• chr8-22404541-A-G
• rs76009801
• NM_001128431.4:c.-15-155A>G

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.-15-155A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0108 in 610,866 control chromosomes in the GnomAD database, including 324 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (259 hom., cov: 31)
  • Exomes 𝑓: 0.0038 (65 hom.)
• Consequence: SLC39A14 NM_001128431.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.352
• 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=-0.9).
• BP6: Variant 8-22404541-A-G is Benign according to our data. Variant chr8-22404541-A-G is described in ClinVar as Benign. ClinVar VariationId is 1249284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.117 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.-15-155A>G		intron	N/A	NP_001121903.1	Q15043-1
	SLC39A14	NM_015359.6	MANE Plus Clinical	c.-15-155A>G		intron	N/A	NP_056174.2	Q15043-3
	SLC39A14	NM_001351657.2		c.16-155A>G		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.-15-155A>G		intron	N/A	ENSP00000352779.5	Q15043-3
	SLC39A14	ENST00000381237.6	TSL:1 MANE Select	c.-15-155A>G		intron	N/A	ENSP00000370635.1	Q15043-1
	SLC39A14	ENST00000240095.10	TSL:1	c.-15-155A>G		intron	N/A	ENSP00000240095.6	Q15043-2

Frequencies

GnomAD3 genomes AF: 0.0332 AC: 4852 AN: 146168 Hom.: 259 Cov.: 31

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0125

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000871

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000223

Gnomad OTH AF: 0.0244

GnomAD4 exome AF: 0.00378 AC: 1756 AN: 464594 Hom.: 65 Cov.: 6 AF XY: 0.00310 AC XY: 758 AN XY: 244764

African (AFR) AF: 0.132 AC: 1339 AN: 10118

American (AMR) AF: 0.00642 AC: 132 AN: 20564

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12342

East Asian (EAS) AF: 0.00 AC: 0 AN: 29668

South Asian (SAS) AF: 0.000158 AC: 6 AN: 37858

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31254

Middle Eastern (MID) AF: 0.00294 AC: 6 AN: 2038

European-Non Finnish (NFE) AF: 0.000176 AC: 52 AN: 296052

Other (OTH) AF: 0.00895 AC: 221 AN: 24700

GnomAD4 genome AF: 0.0331 AC: 4848 AN: 146272 Hom.: 259 Cov.: 31 AF XY: 0.0328 AC XY: 2340 AN XY: 71288

African (AFR) AF: 0.120 AC: 4597 AN: 38232

American (AMR) AF: 0.0124 AC: 183 AN: 14712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 4960

South Asian (SAS) AF: 0.000870 AC: 4 AN: 4598

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9842

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.000223 AC: 15 AN: 67262

Other (OTH) AF: 0.0242 AC: 49 AN: 2028

Alfa AF: 0.0429 Hom.: 36

Bravo AF: 0.0370

Asia WGS AF: 0.00693 AC: 24 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	-0.90
CADD	Benign	7.9
DANN	Benign	0.35
PhyloP100		0.35
PromoterAI		0.010	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs76009801; hg19: chr8-22262054;