rs6597

Variant names:

• chr16-681725-T-G
• rs6597
• ENST00000567120.5:n.2151A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000567120.5(JMJD8):​n.2151A>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.147 in 1,550,620 control chromosomes in the GnomAD database, including 18,434 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1304 hom., cov: 33)
  • Exomes 𝑓: 0.15 (17130 hom.)
• Consequence: JMJD8 ENST00000567120.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.309
• Publications: 37 publications found

Genes affected

JMJD8 (HGNC:14148): (jumonji domain containing 8) Involved in several processes, including positive regulation of I-kappaB kinase/NF-kappaB signaling; positive regulation of sprouting angiogenesis; and regulation of glycolytic process. Located in endoplasmic reticulum lumen and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

STUB1 (HGNC:11427): (STIP1 homology and U-box containing protein 1) This gene encodes a protein containing tetratricopeptide repeat and a U-box that functions as a ubiquitin ligase/cochaperone. The encoded protein binds to and ubiquitinates shock cognate 71 kDa protein (Hspa8) and DNA polymerase beta (Polb), among other targets. Mutations in this gene cause spinocerebellar ataxia, autosomal recessive 16. Alternative splicing results in multiple transcript variants. There is a pseudogene for this gene on chromosome 2. [provided by RefSeq, Jun 2014]

STUB1 Gene-Disease associations (from GenCC):

• spinocerebellar ataxia 48

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal recessive spinocerebellar ataxia 16

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 16-681725-T-G is Benign according to our data. Variant chr16-681725-T-G is described in ClinVar as Benign. ClinVar VariationId is 1222578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.254 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JMJD8	NM_001005920.4	c.*1069A>C		3_prime_UTR_variant	Exon 9 of 9	ENST00000609261.6	NP_001005920.3
STUB1	NM_005861.4	c.525-68T>G		intron_variant	Intron 3 of 6	ENST00000219548.9	NP_005852.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JMJD8	ENST00000609261.6	c.*1069A>C		3_prime_UTR_variant	Exon 9 of 9	1	NM_001005920.4	ENSP00000477481.1
STUB1	ENST00000219548.9	c.525-68T>G		intron_variant	Intron 3 of 6	1	NM_005861.4	ENSP00000219548.4

Frequencies

GnomAD3 genomes AF: 0.122 AC: 18614 AN: 152110 Hom.: 1305 Cov.: 33

Gnomad AFR AF: 0.0887

Gnomad AMI AF: 0.171

Gnomad AMR AF: 0.0878

Gnomad ASJ AF: 0.0974

Gnomad EAS AF: 0.00733

Gnomad SAS AF: 0.265

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.152

Gnomad OTH AF: 0.0986

GnomAD4 exome AF: 0.150 AC: 209126 AN: 1398392 Hom.: 17130 Cov.: 28 AF XY: 0.152 AC XY: 104850 AN XY: 688228

African (AFR) AF: 0.0836 AC: 2686 AN: 32114

American (AMR) AF: 0.0564 AC: 2280 AN: 40456

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 2353 AN: 22688

East Asian (EAS) AF: 0.00328 AC: 128 AN: 38970

South Asian (SAS) AF: 0.252 AC: 19765 AN: 78444

European-Finnish (FIN) AF: 0.111 AC: 5547 AN: 50022

Middle Eastern (MID) AF: 0.105 AC: 447 AN: 4240

European-Non Finnish (NFE) AF: 0.156 AC: 167798 AN: 1073916

Other (OTH) AF: 0.141 AC: 8122 AN: 57542

GnomAD4 genome AF: 0.122 AC: 18613 AN: 152228 Hom.: 1304 Cov.: 33 AF XY: 0.122 AC XY: 9085 AN XY: 74426

African (AFR) AF: 0.0885 AC: 3675 AN: 41548

American (AMR) AF: 0.0877 AC: 1342 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0974 AC: 338 AN: 3470

East Asian (EAS) AF: 0.00734 AC: 38 AN: 5174

South Asian (SAS) AF: 0.266 AC: 1282 AN: 4824

European-Finnish (FIN) AF: 0.116 AC: 1232 AN: 10606

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.152 AC: 10317 AN: 67988

Other (OTH) AF: 0.0975 AC: 206 AN: 2112

Alfa AF: 0.139 Hom.: 3455

Bravo AF: 0.115

Asia WGS AF: 0.107 AC: 377 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 25, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.4
DANN	Benign	0.48
PhyloP100		0.31
PromoterAI		-0.031	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs6597; hg19: chr16-731725; COSMIC: COSV105003624; COSMIC: COSV105003624;