11-90035435-C-T

Variant names:

• chr11-90035435-C-T
• rs748897739
• NM_001195234.1:c.224C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001195234.1(TRIM49C):​c.224C>T​(p.Ser75Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000066 in 1,364,530 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 19)
  • Exomes 𝑓: 0.0000066 (1 hom.)
• Consequence: TRIM49C NM_001195234.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.945

Genes affected

TRIM49C (HGNC:38877): (tripartite motif containing 49C) Predicted to enable ubiquitin protein ligase activity. Predicted to be involved in innate immune response; protein ubiquitination; and regulation of gene expression. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.079000086).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIM49C	NM_001195234.1	c.224C>T	p.Ser75Phe	missense_variant	Exon 3 of 8	ENST00000448984.1	NP_001182163.1
TRIM49C	XM_024448656.2	c.224C>T	p.Ser75Phe	missense_variant	Exon 1 of 6		XP_024304424.1
TRIM49C	XM_017018126.2	c.224C>T	p.Ser75Phe	missense_variant	Exon 1 of 5		XP_016873615.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIM49C	ENST00000448984.1	c.224C>T	p.Ser75Phe	missense_variant	Exon 3 of 8	1	NM_001195234.1	ENSP00000388299.1

Frequencies

GnomAD3 genomes Cov.: 19

GnomAD4 exome AF: 0.00000660 AC: 9 AN: 1364530 Hom.: 1 Cov.: 33 AF XY: 0.00000442 AC XY: 3 AN XY: 679308

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000158

GnomAD4 genome Cov.: 19

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.224C>T (p.S75F) alteration is located in exon 3 (coding exon 1) of the TRIM49C gene. This alteration results from a C to T substitution at nucleotide position 224, causing the serine (S) at amino acid position 75 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	1.3
DANN	Benign	0.48
DEOGEN2	Benign	0.092	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0016	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.5	M
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.16
Sift	Benign	0.13	T
Sift4G	Benign	0.12	T
Polyphen		0.044	B
Vest4		0.10
MutPred		0.43		Loss of phosphorylation at S75 (P = 0.0499);
MVP		0.12
MPC		1.9
ClinPred		0.056	T
GERP RS		-1.5
Varity_R		0.072
gMVP		0.046

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

LitVar

Other links and lift over

dbSNP: rs748897739; hg19: chr11-89768603;