chr5-14393512-C-T

Variant names:

• chr5-14393512-C-T
• rs10065203
• NM_007118.4:c.4219-526C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_007118.4(TRIO):​c.4219-526C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.259 in 152,124 control chromosomes in the GnomAD database, including 6,217 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.26 (6217 hom., cov: 32)
• Consequence: TRIO NM_007118.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.169
• Publications: 7 publications found

Genes affected

TRIO (HGNC:12303): (trio Rho guanine nucleotide exchange factor) This gene encodes a large protein that functions as a GDP to GTP exchange factor. This protein promotes the reorganization of the actin cytoskeleton, thereby playing a role in cell migration and growth. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

TRIO Gene-Disease associations (from GenCC):

• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Illumina
• intellectual developmental disorder, autosomal dominant 63, with macrocephaly

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics
• micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.351 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007118.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIO	NM_007118.4	MANE Select	c.4219-526C>T		intron	N/A	NP_009049.2
	TRIO	NR_134469.2		n.4603-526C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIO	ENST00000344204.9	TSL:1 MANE Select	c.4219-526C>T		intron	N/A	ENSP00000339299.4
	TRIO	ENST00000515144.5	TSL:1	n.3137-526C>T		intron	N/A
	TRIO	ENST00000513206.5	TSL:5	c.3418-526C>T		intron	N/A	ENSP00000426342.2

Frequencies

GnomAD3 genomes AF: 0.259 AC: 39348 AN: 152006 Hom.: 6224 Cov.: 32

Gnomad AFR AF: 0.0882

Gnomad AMI AF: 0.318

Gnomad AMR AF: 0.203

Gnomad ASJ AF: 0.229

Gnomad EAS AF: 0.281

Gnomad SAS AF: 0.173

Gnomad FIN AF: 0.423

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.355

Gnomad OTH AF: 0.257

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.259 AC: 39338 AN: 152124 Hom.: 6217 Cov.: 32 AF XY: 0.260 AC XY: 19335 AN XY: 74344

African (AFR) AF: 0.0879 AC: 3648 AN: 41504

American (AMR) AF: 0.203 AC: 3097 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.229 AC: 794 AN: 3470

East Asian (EAS) AF: 0.280 AC: 1452 AN: 5182

South Asian (SAS) AF: 0.174 AC: 837 AN: 4822

European-Finnish (FIN) AF: 0.423 AC: 4467 AN: 10552

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.355 AC: 24151 AN: 67990

Other (OTH) AF: 0.256 AC: 541 AN: 2110

Alfa AF: 0.313 Hom.: 14918

Bravo AF: 0.237

Asia WGS AF: 0.193 AC: 671 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	2.3
DANN	Benign	0.24
PhyloP100		0.17
Mutation Taster		=100/0	polymorphism (auto)

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: rs10065203; hg19: chr5-14393621;