NM_012141.3:c.2535A>G

Variant names:

• chr13-51367840-T-C
• rs149924575
• NM_012141.3:c.2535A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BP7

The NM_012141.3(INTS6):​c.2535A>G​(p.Leu845Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000428 in 1,594,134 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00034 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00044 (1 hom.)
• Consequence: INTS6 NM_012141.3 synonymous
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.857
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 13-51367840-T-C is Benign according to our data. Variant chr13-51367840-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3034712.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=0.857 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INTS6	NM_012141.3	c.2535A>G	p.Leu845Leu	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.2535A>G	p.Leu845Leu	synonymous_variant	Exon 17 of 18	1	NM_012141.3	ENSP00000310260.4

Frequencies

GnomAD3 genomes AF: 0.000348 AC: 53 AN: 152116 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000486

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000510 AC: 121 AN: 237102 AF XY: 0.000617

Gnomad AFR exome AF: 0.0000639

Gnomad AMR exome AF: 0.000229

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000467

Gnomad NFE exome AF: 0.000768

Gnomad OTH exome AF: 0.000872

GnomAD4 exome AF: 0.000438 AC: 631 AN: 1441900 Hom.: 1 Cov.: 27 AF XY: 0.000484 AC XY: 347 AN XY: 717466

African (AFR) AF: 0.000122 AC: 4 AN: 32654

American (AMR) AF: 0.000313 AC: 13 AN: 41562

Ashkenazi Jewish (ASJ) AF: 0.0000387 AC: 1 AN: 25834

East Asian (EAS) AF: 0.00 AC: 0 AN: 39028

South Asian (SAS) AF: 0.000944 AC: 78 AN: 82632

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53244

Middle Eastern (MID) AF: 0.00478 AC: 27 AN: 5650

European-Non Finnish (NFE) AF: 0.000417 AC: 459 AN: 1101724

Other (OTH) AF: 0.000823 AC: 49 AN: 59572

GnomAD4 genome AF: 0.000342 AC: 52 AN: 152234 Hom.: 1 Cov.: 32 AF XY: 0.000403 AC XY: 30 AN XY: 74444

African (AFR) AF: 0.0000722 AC: 3 AN: 41576

American (AMR) AF: 0.000262 AC: 4 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000486 AC: 33 AN: 67960

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000443 Hom.: 0

Bravo AF: 0.000453

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

INTS6-related disorder Benign:1

Jul 30, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely 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	-0.45
CADD	Benign	8.6
DANN	Benign	0.83
PhyloP100		0.86
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs149924575; hg19: chr13-51941976;