22-37765800-C-A

Variant names:

• chr22-37765800-C-A
• rs534215753
• NM_001039141.3:c.6455C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001039141.3(TRIOBP):​c.6455C>A​(p.Thr2152Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000695 in 1,438,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. T2152M) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: TRIOBP NM_001039141.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.85
• Publications: 1 publications found

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]

TRIOBP Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 28

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet

ACMG classification

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=0.242865).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001039141.3. 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
	TRIOBP	NM_001039141.3	MANE Select	c.6455C>A	p.Thr2152Lys	missense	Exon 18 of 24	NP_001034230.1	Q9H2D6-1
	TRIOBP	NM_007032.5		c.1316C>A	p.Thr439Lys	missense	Exon 8 of 14	NP_008963.3	Q9H2D6-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIOBP	ENST00000644935.1	MANE Select	c.6455C>A	p.Thr2152Lys	missense	Exon 18 of 24	ENSP00000496394.1	Q9H2D6-1
	TRIOBP	ENST00000403663.6	TSL:1	c.1316C>A	p.Thr439Lys	missense	Exon 8 of 14	ENSP00000386026.2	Q9H2D6-7
	TRIOBP	ENST00000344404.10	TSL:2	n.*5938C>A		non_coding_transcript_exon	Exon 16 of 22	ENSP00000340312.6	H7BXW4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.95e-7 AC: 1 AN: 1438820 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 714484

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33140

American (AMR) AF: 0.00 AC: 0 AN: 42286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25820

East Asian (EAS) AF: 0.00 AC: 0 AN: 38766

South Asian (SAS) AF: 0.00 AC: 0 AN: 83482

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4860

European-Non Finnish (NFE) AF: 9.06e-7 AC: 1 AN: 1104352

Other (OTH) AF: 0.00 AC: 0 AN: 59500

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		5.8
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.15
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.97	D
Vest4		0.58
MutPred		0.12		Gain of ubiquitination at T2152 (P = 0.0054)
MVP		0.42
MPC		0.53
ClinPred		0.99	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.62
gMVP		0.44
Mutation Taster		=90/10	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs534215753; hg19: chr22-38161807;