Genetic Variant NM_033547.4:c.2483C>G (chr11-77891428-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_033547.4(INTS4):c.2483C>G(p.Ala828Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,300 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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. A828V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

INTS4
NM_033547.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.67

Publications

0 publications found

Variant links:

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]

INTS4 links:

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]

AAMDC links:

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ACMG classification

Classification was made for transcript

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=0.19376406).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INTS4	NM_033547.4 link	c.2483C>G	p.Ala828Gly	missense_variant	Exon 21 of 23	ENST00000534064.6	NP_291025.3	Q96HW7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INTS4	ENST00000534064.6 link	c.2483C>G	p.Ala828Gly	missense_variant	Exon 21 of 23	1	NM_033547.4	ENSP00000434466.1		Q96HW7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461300

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726916

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44662

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86112

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111728

Other (OTH)

AF:

0.00

AC:

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.058

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.083

T;.

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.23

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

D;D

M_CAP

Benign

0.0084

MetaRNN

Benign

0.19

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.2

L;.

PhyloP100

7.7

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.7

N;N

REVEL

Benign

0.14

Sift

Benign

0.054

T;T

Sift4G

Benign

0.15

T;T

Polyphen

0.19

B;.

Vest4

0.30

MutPred

0.28

Gain of relative solvent accessibility (P = 0.005);.;

MVP

0.35

MPC

0.79

ClinPred

0.87

GERP RS

4.2

Varity_R

0.20

gMVP

0.23

Mutation Taster

=87/13

polymorphism

(source)

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

Publications

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NM_033547.4:c.2483C>G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over