22-37735269-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001039141.3(TRIOBP):c.4933G>T(p.Ala1645Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,456,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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. A1645T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TRIOBP NM_001039141.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.85

Genes affected

TRIOBP (HGNC:17009): (TRIO and F-actin binding protein) This gene encodes a protein with an N-terminal pleckstrin homology domain and a C-terminal coiled-coil region. The protein interacts with trio, which is involved with neural tissue development and controlling actin cytoskeleton organization, cell motility and cell growth. The protein also associates with F-actin and stabilizes F-actin structures. Mutations in this gene have been associated with a form of autosomal recessive nonsyndromic deafness. Multiple alternatively spliced transcript variants that would encode different isoforms have been found for this gene, however some transcripts may be subject to nonsense-mediated decay (NMD). [provided by RefSeq, Nov 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.063661784).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIOBP	NM_001039141.3	c.4933G>T	p.Ala1645Ser	missense_variant	9/24	ENST00000644935.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIOBP	ENST00000644935.1	c.4933G>T	p.Ala1645Ser	missense_variant	9/24		NM_001039141.3	A2
TRIOBP	ENST00000344404.10	c.*4416G>T		3_prime_UTR_variant, NMD_transcript_variant	7/22	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1456848 Hom.: 0 Cov.: 36 AF XY: 0.00000276 AC XY: 2 AN XY: 723700

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: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	15
Dann	Benign	0.96
DEOGEN2	Benign	0.011	T;T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.49	N
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.064	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.18	N;.
REVEL	Benign	0.095
Sift	Uncertain	0.0080	D;.
Sift4G	Benign	0.11	T;.
Polyphen		0.25	B;B
Vest4		0.043
MutPred		0.045		Gain of glycosylation at A1645 (P = 0.0388);Gain of glycosylation at A1645 (P = 0.0388);
MVP		0.33
MPC		0.14
ClinPred		0.21	T
GERP RS		4.3
Varity_R		0.067
gMVP		0.049

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1427161894; hg19: chr22-38131276;