chr5-14386546-T-C

Variant names:

• chr5-14386546-T-C
• rs42259
• NM_007118.4:c.3571-892T>C

Variant summary

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

The NM_007118.4(TRIO):​c.3571-892T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.838 in 152,208 control chromosomes in the GnomAD database, including 53,652 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 0.84 (53652 hom., cov: 32)
• Consequence: TRIO NM_007118.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.540
• Publications: 6 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=-0.95).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.84 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIO	NM_007118.4	c.3571-892T>C		intron_variant	Intron 21 of 56	ENST00000344204.9	NP_009049.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIO	ENST00000344204.9	c.3571-892T>C		intron_variant	Intron 21 of 56	1	NM_007118.4	ENSP00000339299.4

Frequencies

GnomAD3 genomes AF: 0.839 AC: 127544 AN: 152092 Hom.: 53629 Cov.: 32

Gnomad AFR AF: 0.836

Gnomad AMI AF: 0.861

Gnomad AMR AF: 0.819

Gnomad ASJ AF: 0.836

Gnomad EAS AF: 0.753

Gnomad SAS AF: 0.708

Gnomad FIN AF: 0.931

Gnomad MID AF: 0.854

Gnomad NFE AF: 0.845

Gnomad OTH AF: 0.837

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

GnomAD4 genome AF: 0.838 AC: 127615 AN: 152208 Hom.: 53652 Cov.: 32 AF XY: 0.839 AC XY: 62397 AN XY: 74384

African (AFR) AF: 0.836 AC: 34694 AN: 41498

American (AMR) AF: 0.819 AC: 12531 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.836 AC: 2902 AN: 3472

East Asian (EAS) AF: 0.753 AC: 3898 AN: 5178

South Asian (SAS) AF: 0.709 AC: 3418 AN: 4822

European-Finnish (FIN) AF: 0.931 AC: 9871 AN: 10600

Middle Eastern (MID) AF: 0.847 AC: 249 AN: 294

European-Non Finnish (NFE) AF: 0.845 AC: 57505 AN: 68026

Other (OTH) AF: 0.835 AC: 1762 AN: 2110

Alfa AF: 0.837 Hom.: 30654

Bravo AF: 0.831

Asia WGS AF: 0.704 AC: 2451 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.6
DANN	Benign	0.72
PhyloP100		-0.54
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: rs42259; hg19: chr5-14386655;