1-1312114-T-C

Variant names:

• chr1-1312114-T-C
• rs12103
• NM_017871.6:c.1641A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The ENST00000435064.6(INTS11):​c.1641A>G​(p.Pro547Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.715 in 1,568,016 control chromosomes in the GnomAD database, including 435,138 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.59 (30166 hom., cov: 25)
  • Exomes 𝑓: 0.73 (404972 hom.)
• Consequence: INTS11 ENST00000435064.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.75
• Publications: 61 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP7: Synonymous conserved (PhyloP=-2.75 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.811 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000435064.6. 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
	INTS11	NM_017871.6	MANE Select	c.1641A>G	p.Pro547Pro	synonymous	Exon 16 of 17	NP_060341.2
	INTS11	NM_001256456.2		c.1659A>G	p.Pro553Pro	synonymous	Exon 18 of 19	NP_001243385.1
	INTS11	NM_001256460.2		c.1554A>G	p.Pro518Pro	synonymous	Exon 17 of 18	NP_001243389.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INTS11	ENST00000435064.6	TSL:1 MANE Select	c.1641A>G	p.Pro547Pro	synonymous	Exon 16 of 17	ENSP00000413493.2
	INTS11	ENST00000323275.10	TSL:1	n.2029A>G		non_coding_transcript_exon	Exon 15 of 16
	INTS11	ENST00000462432.5	TSL:1	n.2444A>G		non_coding_transcript_exon	Exon 12 of 13

Frequencies

GnomAD3 genomes AF: 0.588 AC: 84374 AN: 143416 Hom.: 30177 Cov.: 25

Gnomad AFR AF: 0.210

Gnomad AMI AF: 0.814

Gnomad AMR AF: 0.537

Gnomad ASJ AF: 0.808

Gnomad EAS AF: 0.0182

Gnomad SAS AF: 0.387

Gnomad FIN AF: 0.753

Gnomad MID AF: 0.795

Gnomad NFE AF: 0.817

Gnomad OTH AF: 0.609

GnomAD2 exomes AF: 0.558 AC: 112752 AN: 202050 AF XY: 0.571

Gnomad AFR exome AF: 0.157

Gnomad AMR exome AF: 0.330

Gnomad ASJ exome AF: 0.821

Gnomad EAS exome AF: 0.0136

Gnomad FIN exome AF: 0.718

Gnomad NFE exome AF: 0.797

Gnomad OTH exome AF: 0.655

GnomAD4 exome AF: 0.728 AC: 1036800 AN: 1424504 Hom.: 404972 Cov.: 54 AF XY: 0.722 AC XY: 508066 AN XY: 704086

African (AFR) AF: 0.172 AC: 5647 AN: 32826

American (AMR) AF: 0.356 AC: 14389 AN: 40406

Ashkenazi Jewish (ASJ) AF: 0.821 AC: 20742 AN: 25260

East Asian (EAS) AF: 0.0114 AC: 434 AN: 38078

South Asian (SAS) AF: 0.399 AC: 32829 AN: 82228

European-Finnish (FIN) AF: 0.732 AC: 36098 AN: 49284

Middle Eastern (MID) AF: 0.721 AC: 3837 AN: 5320

European-Non Finnish (NFE) AF: 0.809 AC: 883359 AN: 1092300

Other (OTH) AF: 0.671 AC: 39465 AN: 58802

GnomAD4 genome AF: 0.588 AC: 84346 AN: 143512 Hom.: 30166 Cov.: 25 AF XY: 0.575 AC XY: 40105 AN XY: 69736

African (AFR) AF: 0.210 AC: 7738 AN: 36904

American (AMR) AF: 0.536 AC: 7364 AN: 13750

Ashkenazi Jewish (ASJ) AF: 0.808 AC: 2781 AN: 3442

East Asian (EAS) AF: 0.0181 AC: 80 AN: 4428

South Asian (SAS) AF: 0.387 AC: 1757 AN: 4540

European-Finnish (FIN) AF: 0.753 AC: 7415 AN: 9842

Middle Eastern (MID) AF: 0.799 AC: 227 AN: 284

European-Non Finnish (NFE) AF: 0.817 AC: 55037 AN: 67400

Other (OTH) AF: 0.600 AC: 1208 AN: 2014

Alfa AF: 0.749 Hom.: 66390

Bravo AF: 0.531

Asia WGS AF: 0.169 AC: 591 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.0060
DANN	Benign	0.32
PhyloP100		-2.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs12103; hg19: chr1-1247494; COSMIC: COSV60088100; COSMIC: COSV60088100;