chr1-219927855-TC-T

Variant names:

• chr1-219927855-TC-T
• rs281860288
• NM_018713.3:c.585delG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_018713.3(SLC30A10):​c.585delG​(p.Thr196ProfsTer17) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SLC30A10 NM_018713.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 0.0440
• Publications: 2 publications found

Genes affected

SLC30A10 (HGNC:25355): (solute carrier family 30 member 10) This gene is highly expressed in the liver and is inducible by manganese. Its protein product appears to be critical in maintaining manganese levels, and has higher specificity for manganese than zinc. Loss of function mutations appear to result in a pleomorphic phenotype, including dystonia and adult-onset parkinsonism. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Mar 2012]

SLC30A10 Gene-Disease associations (from GenCC):

• cirrhosis - dystonia - polycythemia - hypermanganesemia syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-219927855-TC-T is Pathogenic according to our data. Variant chr1-219927855-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 30887.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC30A10	NM_018713.3	c.585delG	p.Thr196ProfsTer17	frameshift_variant	Exon 1 of 4	ENST00000366926.4	NP_061183.2
SLC30A10	NM_001416005.1	c.-129delG		5_prime_UTR_variant	Exon 1 of 4		NP_001402934.1
SLC30A10	NM_001376929.1	c.452-751delG		intron_variant	Intron 1 of 3		NP_001363858.1
SLC30A10	NM_001416004.1	c.-786delG		upstream_gene_variant			NP_001402933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC30A10	ENST00000366926.4	c.585delG	p.Thr196ProfsTer17	frameshift_variant	Exon 1 of 4	1	NM_018713.3	ENSP00000355893.4
SLC30A10	ENST00000356609.2	n.585delG		non_coding_transcript_exon_variant	Exon 1 of 4	1		ENSP00000349018.2
SLC30A10	ENST00000696608.1	c.452-751delG		intron_variant	Intron 1 of 3			ENSP00000512752.1
SLC30A10	ENST00000484239.5	n.81-751delG		intron_variant	Intron 1 of 8	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1393488 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 688056

African (AFR) AF: 0.00 AC: 0 AN: 29404

American (AMR) AF: 0.00 AC: 0 AN: 35642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24766

East Asian (EAS) AF: 0.00 AC: 0 AN: 33988

South Asian (SAS) AF: 0.00 AC: 0 AN: 79008

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49286

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5636

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078094

Other (OTH) AF: 0.00 AC: 0 AN: 57664

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypermanganesemia with dystonia, polycythemia, and cirrhosis Pathogenic:1 Other:1

Mar 09, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

not provided Pathogenic:1

Aug 09, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.044
Mutation Taster		=12/188	disease causing (ClinVar)

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: rs281860288; hg19: chr1-220101197;