chr1-219915173-G-A

Position:

• chr1-219915173-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_018713.3(SLC30A10):​c.*276C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0226 in 426,646 control chromosomes in the GnomAD database, including 163 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (66 hom., cov: 32)
  • Exomes 𝑓: 0.023 (97 hom.)
• Consequence: SLC30A10 NM_018713.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.213

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 1-219915173-G-A is Benign according to our data. Variant chr1-219915173-G-A is described in ClinVar as [Benign]. Clinvar id is 295580.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 = 0.0212 (3228/152238) while in subpopulation NFE AF= 0.0289 (1969/68016). AF 95% confidence interval is 0.0279. There are 66 homozygotes in gnomad4. There are 1713 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 66 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC30A10	NM_018713.3	c.*276C>T		3_prime_UTR_variant	4/4	ENST00000366926.4	NP_061183.2
SLC30A10	NM_001376929.1	c.*276C>T		3_prime_UTR_variant	4/4		NP_001363858.1
SLC30A10	NM_001416004.1	c.*276C>T		3_prime_UTR_variant	3/3		NP_001402933.1
SLC30A10	NM_001416005.1	c.*276C>T		3_prime_UTR_variant	4/4		NP_001402934.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC30A10	ENST00000366926.4	c.*276C>T		3_prime_UTR_variant	4/4	1	NM_018713.3	ENSP00000355893	P3

Frequencies

GnomAD3 genomes AF: 0.0212 AC: 3232 AN: 152120 Hom.: 66 Cov.: 32

Gnomad AFR AF: 0.00521

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0121

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.0166

Gnomad FIN AF: 0.0662

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0290

Gnomad OTH AF: 0.0177

GnomAD4 exome AF: 0.0233 AC: 6394 AN: 274408 Hom.: 97 Cov.: 2 AF XY: 0.0229 AC XY: 3303 AN XY: 143978

Gnomad4 AFR exome AF: 0.00472

Gnomad4 AMR exome AF: 0.00868

Gnomad4 ASJ exome AF: 0.0133

Gnomad4 EAS exome AF: 0.000114

Gnomad4 SAS exome AF: 0.0194

Gnomad4 FIN exome AF: 0.0499

Gnomad4 NFE exome AF: 0.0266

Gnomad4 OTH exome AF: 0.0208

GnomAD4 genome AF: 0.0212 AC: 3228 AN: 152238 Hom.: 66 Cov.: 32 AF XY: 0.0230 AC XY: 1713 AN XY: 74428

Gnomad4 AFR AF: 0.00517

Gnomad4 AMR AF: 0.0121

Gnomad4 ASJ AF: 0.0112

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0164

Gnomad4 FIN AF: 0.0662

Gnomad4 NFE AF: 0.0289

Gnomad4 OTH AF: 0.0175

Alfa AF: 0.0133 Hom.: 4

Bravo AF: 0.0161

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hypermanganesemia with dystonia, polycythemia, and cirrhosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.0
DANN	Benign	0.57

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

Publications

LitVar

Other links and lift over

dbSNP: rs138571819; hg19: chr1-220088515;