1-219928175-A-G

Position:

• chr1-219928175-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_018713.3(SLC30A10):​c.266T>C​(p.Leu89Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC30A10 NM_018713.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 3.55

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 1-219928175-A-G is Pathogenic according to our data. Variant chr1-219928175-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 30886.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-219928175-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC30A10	NM_018713.3	c.266T>C	p.Leu89Pro	missense_variant	1/4	ENST00000366926.4	NP_061183.2
SLC30A10	NM_001416005.1	c.-448T>C		5_prime_UTR_variant	1/4		NP_001402934.1
SLC30A10	NM_001376929.1	c.452-1070T>C		intron_variant			NP_001363858.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC30A10	ENST00000366926.4	c.266T>C	p.Leu89Pro	missense_variant	1/4	1	NM_018713.3	ENSP00000355893	P3
SLC30A10	ENST00000356609.2	c.266T>C	p.Leu89Pro	missense_variant, NMD_transcript_variant	1/4	1		ENSP00000349018
SLC30A10	ENST00000696608.1	c.452-1070T>C		intron_variant				ENSP00000512752	A2
SLC30A10	ENST00000484239.5	n.81-1070T>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 09, 2012	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Pathogenic	4.8	H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.85		Loss of stability (P = 0.0258);
MVP		0.85
MPC		3.5
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.98
gMVP		1.0

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: rs281860284; hg19: chr1-220101517;