22-37771660-G-T

Variant names:

• chr22-37771660-G-T
• NM_001039141.3:c.6860G>T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_001039141.3(TRIOBP):​c.6860G>T​(p.Arg2287Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R2287H) has been classified as Pathogenic.

• 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: 9.28

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-37771660-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.821

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIOBP	NM_001039141.3	c.6860G>T	p.Arg2287Leu	missense_variant	Exon 22 of 24	ENST00000644935.1	NP_001034230.1
TRIOBP	NM_007032.5	c.1721G>T	p.Arg574Leu	missense_variant	Exon 12 of 14		NP_008963.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIOBP	ENST00000644935.1	c.6860G>T	p.Arg2287Leu	missense_variant	Exon 22 of 24		NM_001039141.3	ENSP00000496394.1
TRIOBP	ENST00000403663.6	c.1721G>T	p.Arg574Leu	missense_variant	Exon 12 of 14	1		ENSP00000386026.2
TRIOBP	ENST00000344404.10	n.*6343G>T		non_coding_transcript_exon_variant	Exon 20 of 22	2		ENSP00000340312.6
TRIOBP	ENST00000344404.10	n.*6343G>T		3_prime_UTR_variant	Exon 20 of 22	2		ENSP00000340312.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461784 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727186

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;T;.
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	.;D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.4	M;M;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.2	D;.;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0010	D;.;D
Sift4G	Pathogenic	0.0	D;.;D
Polyphen		1.0	D;D;.
Vest4		0.79
MutPred		0.31		Loss of ubiquitination at K2289 (P = 0.0431);Loss of ubiquitination at K2289 (P = 0.0431);.;
MVP		0.54
MPC		0.62
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.50
gMVP		0.34

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-38167667;