22-37735388-G-T

Variant names:

• chr22-37735388-G-T
• rs41283241
• NM_001039141.3:c.5052G>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001039141.3(TRIOBP):​c.5052G>T​(p.Thr1684Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00761 in 1,603,936 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1684T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0064 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0077 (51 hom.)
• Consequence: TRIOBP NM_001039141.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.322
• 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), PanelApp Australia
• hearing loss, autosomal recessive

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 22-37735388-G-T is Benign according to our data. Variant chr22-37735388-G-T is described in ClinVar as Benign. ClinVar VariationId is 43858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.322 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00638 (972/152314) while in subpopulation AMR AF = 0.00921 (141/15308). AF 95% confidence interval is 0.00803. There are 3 homozygotes in GnomAd4. There are 442 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.5052G>T	p.Thr1684Thr	synonymous	Exon 9 of 24	NP_001034230.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIOBP	ENST00000644935.1	MANE Select	c.5052G>T	p.Thr1684Thr	synonymous	Exon 9 of 24	ENSP00000496394.1
	TRIOBP	ENST00000344404.10	TSL:2	n.*4535G>T		non_coding_transcript_exon	Exon 7 of 22	ENSP00000340312.6
	TRIOBP	ENST00000344404.10	TSL:2	n.*4535G>T		3_prime_UTR	Exon 7 of 22	ENSP00000340312.6

Frequencies

GnomAD3 genomes AF: 0.00639 AC: 973 AN: 152196 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00241

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.00922

Gnomad ASJ AF: 0.0202

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00862

Gnomad OTH AF: 0.00717

GnomAD2 exomes AF: 0.00744 AC: 1653 AN: 222120 AF XY: 0.00752

Gnomad AFR exome AF: 0.00251

Gnomad AMR exome AF: 0.0102

Gnomad ASJ exome AF: 0.0207

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00162

Gnomad NFE exome AF: 0.00966

Gnomad OTH exome AF: 0.0116

GnomAD4 exome AF: 0.00774 AC: 11233 AN: 1451622 Hom.: 51 Cov.: 36 AF XY: 0.00785 AC XY: 5660 AN XY: 721432

African (AFR) AF: 0.00301 AC: 100 AN: 33258

American (AMR) AF: 0.0105 AC: 450 AN: 42864

Ashkenazi Jewish (ASJ) AF: 0.0194 AC: 503 AN: 25918

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39170

South Asian (SAS) AF: 0.00265 AC: 226 AN: 85176

European-Finnish (FIN) AF: 0.00224 AC: 116 AN: 51886

Middle Eastern (MID) AF: 0.0125 AC: 72 AN: 5750

European-Non Finnish (NFE) AF: 0.00830 AC: 9197 AN: 1107636

Other (OTH) AF: 0.00947 AC: 568 AN: 59964

GnomAD4 genome AF: 0.00638 AC: 972 AN: 152314 Hom.: 3 Cov.: 33 AF XY: 0.00593 AC XY: 442 AN XY: 74480

African (AFR) AF: 0.00243 AC: 101 AN: 41564

American (AMR) AF: 0.00921 AC: 141 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0202 AC: 70 AN: 3472

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5190

South Asian (SAS) AF: 0.00394 AC: 19 AN: 4824

European-Finnish (FIN) AF: 0.00169 AC: 18 AN: 10628

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00860 AC: 585 AN: 68008

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.00807 Hom.: 7

Bravo AF: 0.00737

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.19
DANN	Benign	0.65
PhyloP100		-0.32
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs41283241; hg19: chr22-38131395;