1-219927933-GC-GCC

Variant names:

• chr1-219927933-G-GC
• rs281860287
• NM_018713.3:c.507dupG

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_018713.3(SLC30A10):​c.507dupG​(p.Pro170AlafsTer46) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000722 in 1,385,512 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. G169G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: SLC30A10 NM_018713.3 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -6.07
• Publications: 0 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: Orphanet, Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 10 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018713.3. 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
	SLC30A10	NM_018713.3	MANE Select	c.507dupG	p.Pro170AlafsTer46	frameshift	Exon 1 of 4	NP_061183.2
	SLC30A10	NM_001416005.1		c.-207dupG		5_prime_UTR	Exon 1 of 4	NP_001402934.1	B3KR19
	SLC30A10	NM_001376929.1		c.452-829dupG		intron	N/A	NP_001363858.1	A0A8Q3WLF3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC30A10	ENST00000366926.4	TSL:1 MANE Select	c.507dupG	p.Pro170AlafsTer46	frameshift	Exon 1 of 4	ENSP00000355893.4	Q6XR72-4
	SLC30A10	ENST00000356609.2	TSL:1	n.507dupG		non_coding_transcript_exon	Exon 1 of 4	ENSP00000349018.2	Q6XR72-3
	SLC30A10	ENST00000886495.1		c.507dupG	p.Pro170AlafsTer62	frameshift	Exon 1 of 4	ENSP00000556554.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.22e-7 AC: 1 AN: 1385512 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 683140

African (AFR) AF: 0.00 AC: 0 AN: 29172

American (AMR) AF: 0.00 AC: 0 AN: 34636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24542

East Asian (EAS) AF: 0.00 AC: 0 AN: 33974

South Asian (SAS) AF: 0.00 AC: 0 AN: 78168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47998

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5620

European-Non Finnish (NFE) AF: 9.31e-7 AC: 1 AN: 1074030

Other (OTH) AF: 0.00 AC: 0 AN: 57372

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-6.1

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: rs281860287; hg19: chr1-220101275;