rs758546717

Variant names:

• chr11-124626940-G-A
• rs758546717
• NM_032811.3:c.628G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-124626940-G-A
• chr11-124626940-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PP2 PP5 BP4

The NM_032811.3(TBRG1):​c.628G>A​(p.Ala210Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000757 in 1,453,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A210S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: TBRG1 NM_032811.3 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.87
• Publications: 1 publications found

Genes affected

TBRG1 (HGNC:29551): (transforming growth factor beta regulator 1) Involved in several processes, including DNA replication; protein localization to nucleoplasm; and protein stabilization. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.8118 (below the threshold of 3.09). Trascript score misZ: 0.037837 (below the threshold of 3.09).
• PP5: Variant 11-124626940-G-A is Pathogenic according to our data. Variant chr11-124626940-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 996584.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.26260912). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032811.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBRG1	NM_032811.3	MANE Select	c.628G>A	p.Ala210Thr	missense	Exon 5 of 9	NP_116200.2	Q3YBR2-1
	TBRG1	NR_016021.2		n.711G>A		non_coding_transcript_exon	Exon 4 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBRG1	ENST00000441174.8	TSL:1 MANE Select	c.628G>A	p.Ala210Thr	missense	Exon 5 of 9	ENSP00000409016.3	Q3YBR2-1
	TBRG1	ENST00000284290.8	TSL:1	n.*8G>A		non_coding_transcript_exon	Exon 4 of 8	ENSP00000284290.4	F8W6N5
	TBRG1	ENST00000438907.3	TSL:1	n.234G>A		non_coding_transcript_exon	Exon 3 of 7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000168 AC: 4 AN: 238408 AF XY: 0.0000156

Gnomad AFR exome AF: 0.0000656

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000757 AC: 11 AN: 1453674 Hom.: 0 Cov.: 31 AF XY: 0.00000831 AC XY: 6 AN XY: 722028

African (AFR) AF: 0.00 AC: 0 AN: 33386

American (AMR) AF: 0.00 AC: 0 AN: 43882

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25920

East Asian (EAS) AF: 0.00 AC: 0 AN: 39568

South Asian (SAS) AF: 0.000131 AC: 11 AN: 84230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53026

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107796

Other (OTH) AF: 0.00 AC: 0 AN: 60108

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	T
Eigen	Benign	0.026
Eigen_PC	Benign	0.086
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.9
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.26
Sift	Benign	0.39	T
Sift4G	Uncertain	0.038	D
Polyphen		0.74	P
Vest4		0.63
MutPred		0.65		Gain of glycosylation at A210 (P = 0.0157)
MVP		0.88
MPC		0.097
ClinPred		0.62	D
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.13
gMVP		0.55
Mutation Taster		=15/85	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs758546717; hg19: chr11-124496836;