NM_001039141.3:c.5393C>G

Variant names:

• chr22-37754890-C-G
• rs876657595
• NM_001039141.3:c.5393C>G

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.5393C>G​(p.Ser1798Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. S1798L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TRIOBP NM_001039141.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.66
• Publications: 0 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=0.24990004).

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.5393C>G	p.Ser1798Trp	missense	Exon 13 of 24	NP_001034230.1	Q9H2D6-1
	TRIOBP	NM_007032.5		c.254C>G	p.Ser85Trp	missense	Exon 3 of 14	NP_008963.3	Q9H2D6-7
	TRIOBP	NM_138632.2		c.254C>G	p.Ser85Trp	missense	Exon 3 of 8	NP_619538.2	Q9H2D6-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIOBP	ENST00000644935.1	MANE Select	c.5393C>G	p.Ser1798Trp	missense	Exon 13 of 24	ENSP00000496394.1	Q9H2D6-1
	TRIOBP	ENST00000403663.6	TSL:1	c.254C>G	p.Ser85Trp	missense	Exon 3 of 14	ENSP00000386026.2	Q9H2D6-7
	TRIOBP	ENST00000407319.7	TSL:1	c.254C>G	p.Ser85Trp	missense	Exon 3 of 8	ENSP00000383913.2	Q9H2D6-6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251474 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

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: 6.84e-7 AC: 1 AN: 1461846 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727224

⚠️ 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: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60394

⚠️ 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.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.0047	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	1.7
DANN	Benign	0.97
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.25	T
MetaSVM	Uncertain	-0.053	T
MutationAssessor	Benign	1.1	L
PhyloP100		-3.7
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.45
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.032	D
Polyphen		0.99	D
Vest4		0.43
MutPred		0.43		Gain of catalytic residue at S1798 (P = 0.0014)
MVP		0.71
MPC		0.52
ClinPred		0.51	D
GERP RS		-4.5
Varity_R		0.059
gMVP		0.29
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs876657595; hg19: chr22-38150897;