1-1312238-C-A

Variant names:

• chr1-1312238-C-A
• rs1179153155
• NM_017871.6:c.1595G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_017871.6(INTS11):​c.1595G>T​(p.Ser532Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000203 in 1,480,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S532N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000079 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: INTS11 NM_017871.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.96
• Publications: 0 publications found

Genes affected

INTS11 (HGNC:26052): (integrator complex subunit 11) The Integrator complex contains at least 12 subunits and associates with the C-terminal domain of RNA polymerase II large subunit (POLR2A; MIM 180660) and mediates the 3-prime end processing of small nuclear RNAs U1 (RNU1; MIM 180680) and U2 (RNU2; MIM 180690). INTS11, or CPSF3L, is the catalytic subunit of the Integrator complex (Baillat et al., 2005 [PubMed 16239144]).[supplied by OMIM, Mar 2008]

INTS11 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• neurodevelopmental disorder with motor and language delay, ocular defects, and brain abnormalities

  Inheritance: AR Classification: MODERATE Submitted by: G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28406715).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017871.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INTS11	NM_017871.6	MANE Select	c.1595G>T	p.Ser532Ile	missense	Exon 15 of 17	NP_060341.2
	INTS11	NM_001256456.2		c.1613G>T	p.Ser538Ile	missense	Exon 17 of 19	NP_001243385.1	Q5TA45-5
	INTS11	NM_001256460.2		c.1508G>T	p.Ser503Ile	missense	Exon 16 of 18	NP_001243389.1	Q5TA45-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INTS11	ENST00000435064.6	TSL:1 MANE Select	c.1595G>T	p.Ser532Ile	missense	Exon 15 of 17	ENSP00000413493.2	Q5TA45-1
	INTS11	ENST00000323275.10	TSL:1	n.1983G>T		non_coding_transcript_exon	Exon 14 of 16
	INTS11	ENST00000462432.5	TSL:1	n.2398G>T		non_coding_transcript_exon	Exon 11 of 13

Frequencies

GnomAD3 genomes AF: 0.00000791 AC: 1 AN: 126488 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000178

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000148 AC: 2 AN: 1353612 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 663952

African (AFR) AF: 0.00 AC: 0 AN: 31944

American (AMR) AF: 0.00 AC: 0 AN: 35240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24426

East Asian (EAS) AF: 0.00 AC: 0 AN: 36442

South Asian (SAS) AF: 0.00 AC: 0 AN: 78418

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45292

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4080

European-Non Finnish (NFE) AF: 0.00000192 AC: 2 AN: 1041510

Other (OTH) AF: 0.00 AC: 0 AN: 56260

GnomAD4 genome AF: 0.00000791 AC: 1 AN: 126488 Hom.: 0 Cov.: 31 AF XY: 0.0000167 AC XY: 1 AN XY: 59860

African (AFR) AF: 0.00 AC: 0 AN: 38174

American (AMR) AF: 0.00 AC: 0 AN: 11572

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2940

East Asian (EAS) AF: 0.00 AC: 0 AN: 5072

South Asian (SAS) AF: 0.00 AC: 0 AN: 4294

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5690

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 144

European-Non Finnish (NFE) AF: 0.0000178 AC: 1 AN: 56202

Other (OTH) AF: 0.00 AC: 0 AN: 1652

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.0
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.093
Sift	Benign	0.14	T
Sift4G	Benign	0.18	T
Polyphen		0.043	B
Vest4		0.51
MutPred		0.51		Loss of disorder (P = 0.0303)
MVP		0.61
MPC		0.036
ClinPred		0.61	D
GERP RS		4.6
Varity_R		0.19
gMVP		0.34
Mutation Taster		=53/47	polymorphism

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: rs1179153155; hg19: chr1-1247618;