rs727503523

Variant names:

• chr22-37757618-C-T
• rs727503523
• NM_001039141.3:c.5693C>T

Your query was ambiguous. Multiple possible variants found:

• chr22-37757618-C-T
• chr22-37757618-C-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.5693C>T​(p.Ser1898Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000442 in 1,582,374 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: TRIOBP NM_001039141.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.04
• 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=0.24269393).

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.5693C>T	p.Ser1898Leu	missense	Exon 16 of 24	NP_001034230.1	Q9H2D6-1
	TRIOBP	NM_007032.5		c.554C>T	p.Ser185Leu	missense	Exon 6 of 14	NP_008963.3	Q9H2D6-7
	TRIOBP	NM_138632.2		c.554C>T	p.Ser185Leu	missense	Exon 6 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.5693C>T	p.Ser1898Leu	missense	Exon 16 of 24	ENSP00000496394.1	Q9H2D6-1
	TRIOBP	ENST00000403663.6	TSL:1	c.554C>T	p.Ser185Leu	missense	Exon 6 of 14	ENSP00000386026.2	Q9H2D6-7
	TRIOBP	ENST00000407319.7	TSL:1	c.554C>T	p.Ser185Leu	missense	Exon 6 of 8	ENSP00000383913.2	Q9H2D6-6

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000503 AC: 1 AN: 198610 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000662

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000350 AC: 5 AN: 1430208 Hom.: 0 Cov.: 32 AF XY: 0.00000282 AC XY: 2 AN XY: 709362

African (AFR) AF: 0.00 AC: 0 AN: 32768

American (AMR) AF: 0.00 AC: 0 AN: 40448

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25564

East Asian (EAS) AF: 0.00 AC: 0 AN: 38080

South Asian (SAS) AF: 0.0000243 AC: 2 AN: 82282

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46756

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

European-Non Finnish (NFE) AF: 0.00000273 AC: 3 AN: 1099200

Other (OTH) AF: 0.00 AC: 0 AN: 59370

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74330

African (AFR) AF: 0.0000483 AC: 2 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.077	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
PhyloP100		2.0
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.15
Sift	Benign	0.088	T
Sift4G	Benign	0.22	T
Polyphen		1.0	D
Vest4		0.40
MutPred		0.18		Loss of phosphorylation at S1898 (P = 0.0438)
MVP		0.48
MPC		0.11
ClinPred		0.70	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.053
gMVP		0.34
Mutation Taster		=67/33	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: rs727503523; hg19: chr22-38153625;