11-77891459-G-C

Variant names:

• chr11-77891459-G-C
• rs963215329
• NM_033547.4:c.2452C>G

Variant summary

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

The NM_033547.4(INTS4):​c.2452C>G​(p.His818Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. H818Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: INTS4 NM_033547.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.63
• Publications: 0 publications found

Genes affected

INTS4 (HGNC:25048): (integrator complex subunit 4) INTS4 is a subunit of the Integrator complex, which associates with the C-terminal domain of RNA polymerase II large subunit (POLR2A; MIM 180660) and mediates 3-prime end processing of small nuclear RNAs U1 (RNU1; MIM 180680) and U2 (RNU2; MIM 180690) (Baillat et al., 2005 [PubMed 16239144]).[supplied by OMIM, Mar 2008]

AAMDC (HGNC:30205): (adipogenesis associated Mth938 domain containing) Predicted to be involved in positive regulation of fat cell differentiation. Predicted to act upstream of or within negative regulation of apoptotic process and positive regulation of transcription by RNA polymerase II. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INTS4	NM_033547.4	c.2452C>G	p.His818Asp	missense_variant	Exon 21 of 23	ENST00000534064.6	NP_291025.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INTS4	ENST00000534064.6	c.2452C>G	p.His818Asp	missense_variant	Exon 21 of 23	1	NM_033547.4	ENSP00000434466.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.0030	T
MetaRNN	Uncertain	0.65	D;D
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.8	L;.
PhyloP100		9.6
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.9	N;N
REVEL	Uncertain	0.33
Sift	Benign	0.088	T;D
Sift4G	Uncertain	0.037	D;D
Polyphen		0.68	P;.
Vest4		0.83
MutPred		0.39		Gain of ubiquitination at K819 (P = 0.0624);.;
MVP		0.34
MPC		1.1
ClinPred		0.94	D
GERP RS		5.0
Varity_R		0.38
gMVP		0.64
Mutation Taster		=39/61	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: rs963215329; hg19: chr11-77602505;