NM_017864.4:c.484A>C

Variant names:

• chr8-94827759-A-C
• rs796052157
• NM_017864.4:c.484A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4 BP6

The NM_017864.4(INTS8):​c.484A>C​(p.Lys162Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: INTS8 NM_017864.4 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 6.91
• Publications: 1 publications found

Genes affected

INTS8 (HGNC:26048): (integrator complex subunit 8) This gene encodes a subunit of the Integrator complex which is involved in the cleavage of small nuclear RNAs U1 and U2 within the nucleus. The encoded protein associates with RNA polymerase II and is recruited to the U1 and U2 small nuclear RNA genes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2012]

INTS8 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with cerebellar hypoplasia and spasticity

  Inheritance: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37739876).
• BP6: Variant 8-94827759-A-C is Benign according to our data. Variant chr8-94827759-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 207857.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017864.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INTS8	NM_017864.4	MANE Select	c.484A>C	p.Lys162Gln	missense	Exon 4 of 27	NP_060334.2
	INTS8	NR_073444.2		n.629A>C		non_coding_transcript_exon	Exon 4 of 29
	INTS8	NR_073445.2		n.629A>C		non_coding_transcript_exon	Exon 4 of 28

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INTS8	ENST00000523731.6	TSL:1 MANE Select	c.484A>C	p.Lys162Gln	missense	Exon 4 of 27	ENSP00000430338.1
	INTS8	ENST00000343161.8	TSL:1	n.484A>C		non_coding_transcript_exon	Exon 4 of 29	ENSP00000343274.4
	INTS8	ENST00000523206.5	TSL:1	n.484A>C		non_coding_transcript_exon	Exon 4 of 28	ENSP00000429452.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	Long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		6.9
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.25
Sift	Uncertain	0.0050	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.58	P
Vest4		0.62
MutPred		0.38		Loss of methylation at K162 (P = 6e-04)
MVP		0.15
MPC		0.56
ClinPred		0.98	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.66
gMVP		0.66
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs796052157; hg19: chr8-95839987;