chr19-10908113-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_199141.2(CARM1):​c.421A>G​(p.Thr141Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

CARM1
NM_199141.2 missense

Scores

2
12
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.01
Variant links:
Genes affected
CARM1 (HGNC:23393): (coactivator associated arginine methyltransferase 1) This gene belongs to the protein arginine methyltransferase (PRMT) family. The encoded enzyme catalyzes the methylation of guanidino nitrogens of arginyl residues of proteins. The enzyme acts specifically on histones and other chromatin-associated proteins and is involved in regulation of gene expression. The enzyme may act in association with other proteins or within multi-protein complexes and may play a role in cell type-specific functions and cell lineage specification. A related pseudogene is located on chromosome 9. [provided by RefSeq, Aug 2013]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CARM1NM_199141.2 linkuse as main transcriptc.421A>G p.Thr141Ala missense_variant 3/16 ENST00000327064.9 NP_954592.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CARM1ENST00000327064.9 linkuse as main transcriptc.421A>G p.Thr141Ala missense_variant 3/161 NM_199141.2 ENSP00000325690 P2Q86X55-3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Neurodevelopmental disorder Uncertain:1
Uncertain significance, criteria provided, single submittercurationBroad Center for Mendelian Genomics, Broad Institute of MIT and HarvardJun 19, 2024The heterozygous p.Thr141Ala variant in CARM1 was identified by our study in 1 individual with a neurodevelopmental disorder. While this gene is still lacking sufficient evidence to establish a gene-disease relationship, we believe this is a possible novel gene candidate for neurodevelopmental disorders. Given the limited information about this gene-disease relationship, the significance of the p.Thr141Ala variant is uncertain. If you have any additional information about functional evidence or other individuals with this phenotype that also have variants in CARM1 we encourage you to reach out to us. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Uncertain
-0.080
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.45
T;.;.
Eigen
Uncertain
0.21
Eigen_PC
Uncertain
0.27
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.83
T;T;T
M_CAP
Benign
0.022
T
MetaRNN
Uncertain
0.46
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.4
M;.;M
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.77
T
PROVEAN
Uncertain
-4.3
D;.;D
REVEL
Benign
0.26
Sift
Uncertain
0.0060
D;.;D
Sift4G
Uncertain
0.013
D;D;D
Polyphen
0.42
B;.;.
Vest4
0.74
MutPred
0.19
Loss of phosphorylation at T141 (P = 0.0738);.;Loss of phosphorylation at T141 (P = 0.0738);
MVP
0.79
MPC
1.5
ClinPred
0.99
D
GERP RS
4.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.43
gMVP
0.77

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-11018789; API