13-51367807-T-C

Variant names:

• chr13-51367807-T-C
• rs61749884
• NM_012141.3:c.2568A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BA1

The NM_012141.3(INTS6):​c.2568A>G​(p.Ser856Ser) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0123 in 1,539,298 control chromosomes in the GnomAD database, including 293 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.011 (26 hom., cov: 32)
  • Exomes 𝑓: 0.012 (267 hom.)
• Consequence: INTS6 NM_012141.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.001075
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.07
• Publications: 5 publications found

Genes affected

INTS6 (HGNC:14879): (integrator complex subunit 6) DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases. The protein encoded by this gene is a DEAD box protein that is part of a complex that interacts with the C-terminus of RNA polymerase II and is involved in 3' end processing of snRNAs. In addition, this gene is a candidate tumor suppressor and is located in the critical region of loss of heterozygosity (LOH). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2015]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 13-51367807-T-C is Benign according to our data. Variant chr13-51367807-T-C is described in ClinVar as [Benign]. Clinvar id is 3037731.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=1.07 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0644 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INTS6	NM_012141.3	c.2568A>G	p.Ser856Ser	splice_region_variant, synonymous_variant	Exon 17 of 18	ENST00000311234.9	NP_036273.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INTS6	ENST00000311234.9	c.2568A>G	p.Ser856Ser	splice_region_variant, synonymous_variant	Exon 17 of 18	1	NM_012141.3	ENSP00000310260.4

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1733 AN: 152130 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.00246

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0155

Gnomad ASJ AF: 0.0416

Gnomad EAS AF: 0.0700

Gnomad SAS AF: 0.0412

Gnomad FIN AF: 0.00395

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.00892

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.0180 AC: 4234 AN: 234920 AF XY: 0.0192

Gnomad AFR exome AF: 0.00207

Gnomad AMR exome AF: 0.0113

Gnomad ASJ exome AF: 0.0364

Gnomad EAS exome AF: 0.0682

Gnomad FIN exome AF: 0.00506

Gnomad NFE exome AF: 0.0102

Gnomad OTH exome AF: 0.0192

GnomAD4 exome AF: 0.0124 AC: 17230 AN: 1387050 Hom.: 267 Cov.: 22 AF XY: 0.0132 AC XY: 9136 AN XY: 693538

African (AFR) AF: 0.00231 AC: 73 AN: 31534

American (AMR) AF: 0.0126 AC: 517 AN: 41184

Ashkenazi Jewish (ASJ) AF: 0.0364 AC: 925 AN: 25444

East Asian (EAS) AF: 0.0650 AC: 2508 AN: 38610

South Asian (SAS) AF: 0.0383 AC: 3108 AN: 81150

European-Finnish (FIN) AF: 0.00514 AC: 273 AN: 53116

Middle Eastern (MID) AF: 0.0262 AC: 131 AN: 5004

European-Non Finnish (NFE) AF: 0.00819 AC: 8623 AN: 1053382

Other (OTH) AF: 0.0186 AC: 1072 AN: 57626

GnomAD4 genome AF: 0.0113 AC: 1728 AN: 152248 Hom.: 26 Cov.: 32 AF XY: 0.0122 AC XY: 907 AN XY: 74442

African (AFR) AF: 0.00245 AC: 102 AN: 41582

American (AMR) AF: 0.0154 AC: 235 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0416 AC: 144 AN: 3464

East Asian (EAS) AF: 0.0704 AC: 365 AN: 5188

South Asian (SAS) AF: 0.0408 AC: 197 AN: 4830

European-Finnish (FIN) AF: 0.00395 AC: 42 AN: 10628

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.00892 AC: 606 AN: 67958

Other (OTH) AF: 0.0114 AC: 24 AN: 2114

Alfa AF: 0.0104 Hom.: 12

Bravo AF: 0.0125

Asia WGS AF: 0.0460 AC: 157 AN: 3458

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

INTS6-related disorder Benign:1

Apr 11, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	14
DANN	Benign	0.84
PhyloP100		1.1
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0011
dbscSNV1_RF	Benign	0.018
SpliceAI score (max)		0.020		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: rs61749884; hg19: chr13-51941943;