13-51365759-C-A

Variant names:

• chr13-51365759-C-A
• rs968997787
• NM_012141.3:c.2657G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012141.3(INTS6):​c.2657G>T​(p.Ser886Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000263 in 151,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S886N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: INTS6 NM_012141.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.66
• Publications: 0 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: 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=0.22031668).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INTS6	NM_012141.3	c.2657G>T	p.Ser886Ile	missense_variant	Exon 18 of 18	ENST00000311234.9	NP_036273.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INTS6	ENST00000311234.9	c.2657G>T	p.Ser886Ile	missense_variant	Exon 18 of 18	1	NM_012141.3	ENSP00000310260.4

Frequencies

GnomAD3 genomes AF: 0.0000264 AC: 4 AN: 151764 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000658

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1393456 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 695824

African (AFR) AF: 0.00 AC: 0 AN: 31522

American (AMR) AF: 0.00 AC: 0 AN: 41234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25142

East Asian (EAS) AF: 0.00 AC: 0 AN: 39022

South Asian (SAS) AF: 0.00 AC: 0 AN: 81520

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52888

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3944

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1060522

Other (OTH) AF: 0.00 AC: 0 AN: 57662

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 151882 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74248

African (AFR) AF: 0.0000723 AC: 3 AN: 41488

American (AMR) AF: 0.0000657 AC: 1 AN: 15226

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67822

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2657G>T (p.S886I) alteration is located in exon 18 (coding exon 18) of the INTS6 gene. This alteration results from a G to T substitution at nucleotide position 2657, causing the serine (S) at amino acid position 886 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	.;T;T;T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.80	T;T;T;T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.22	T;T;T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.5	.;M;.;.
PhyloP100		4.7
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.9	N;N;N;N
REVEL	Benign	0.18
Sift	Uncertain	0.0060	D;D;D;D
Sift4G	Uncertain	0.017	D;D;D;D
Polyphen		0.97	.;D;.;.
Vest4		0.45
MutPred		0.26		.;Loss of disorder (P = 0.0585);.;.;
MVP		0.55
MPC		0.56
ClinPred		0.93	D
GERP RS		5.5
Varity_R		0.26
gMVP		0.58
Mutation Taster		=46/54	disease causing

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: rs968997787; hg19: chr13-51939895;