5-69115971-GTTATC-G

Position:

• chr5-69115971-GTTATC-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The ENST00000396591.8(SLC30A5):​c.832_836del​(p.Ile278PhefsTer33) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC30A5 ENST00000396591.8 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.95

Genes affected

SLC30A5 (HGNC:19089): (solute carrier family 30 member 5) This gene encodes a member of the SLC30A/ZnT family of zinc transporter proteins. ZnT proteins mediate both cellular zinc efflux and zinc sequestration into membrane-bound organelles. The encoded protein plays a role in the early secretory pathway as a heterodimer with zinc transporter 6, and may also regulate zinc sequestration into secretory granules of pancreatic beta cells. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 19. [provided by RefSeq, Oct 2011]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 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 5-69115971-GTTATC-G is Pathogenic according to our data. Variant chr5-69115971-GTTATC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 976212.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC30A5	NM_022902.5	c.832_836del	p.Ile278PhefsTer33	frameshift_variant	9/16	ENST00000396591.8	NP_075053.2
SLC30A5	XM_005248569.4	c.709_713del	p.Ile237PhefsTer33	frameshift_variant	8/15		XP_005248626.1
SLC30A5	XM_006714672.5	c.832_836del	p.Ile278PhefsTer33	frameshift_variant	9/15		XP_006714735.1
SLC30A5	XM_017009749.2	c.709_713del	p.Ile237PhefsTer33	frameshift_variant	8/14		XP_016865238.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC30A5	ENST00000396591.8	c.832_836del	p.Ile278PhefsTer33	frameshift_variant	9/16	1	NM_022902.5	ENSP00000379836	P1
SLC30A5	ENST00000507354.5	n.1030_1034del		non_coding_transcript_exon_variant	6/11	1
	ENST00000690195.2	n.683-574_683-570del		intron_variant, non_coding_transcript_variant
	ENST00000504129.1	n.609-574_609-570del		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypertrophic cardiomyopathy;C0020305:Hydrops fetalis;C0238044:Concentric hypertrophic cardiomyopathy;C1839832:Noncompaction cardiomyopathy;C1866048:Severe hydrops fetalis Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Institute of Human Genetics, University of Leipzig Medical Center

Jan 29, 2020

Variant found homozygous in three siblings with similar phenotype -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1746359403; hg19: chr5-68411798;