chr5-14417820-A-G

Variant names:

• chr5-14417820-A-G
• rs42404
• NM_007118.4:c.4960-1958A>G

Variant summary

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

The NM_007118.4(TRIO):​c.4960-1958A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.293 in 152,144 control chromosomes in the GnomAD database, including 7,200 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 0.29 (7200 hom., cov: 33)
• Consequence: TRIO NM_007118.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.90
• 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: Illumina, ClinGen
• 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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

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 (AMR) allele frequency at 95% confidence interval = 0.353 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIO	NM_007118.4	MANE Select	c.4960-1958A>G		intron	N/A	NP_009049.2
	TRIO	NR_134469.2		n.5344-1958A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIO	ENST00000344204.9	TSL:1 MANE Select	c.4960-1958A>G		intron	N/A	ENSP00000339299.4	O75962-1
	TRIO	ENST00000515144.5	TSL:1	n.3878-1958A>G		intron	N/A
	TRIO	ENST00000513206.5	TSL:5	c.4159-1958A>G		intron	N/A	ENSP00000426342.2	E7EPJ7

Frequencies

GnomAD3 genomes AF: 0.293 AC: 44567 AN: 152026 Hom.: 7206 Cov.: 33

Gnomad AFR AF: 0.190

Gnomad AMI AF: 0.445

Gnomad AMR AF: 0.361

Gnomad ASJ AF: 0.531

Gnomad EAS AF: 0.107

Gnomad SAS AF: 0.327

Gnomad FIN AF: 0.237

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.346

Gnomad OTH AF: 0.316

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

GnomAD4 genome AF: 0.293 AC: 44581 AN: 152144 Hom.: 7200 Cov.: 33 AF XY: 0.291 AC XY: 21625 AN XY: 74370

African (AFR) AF: 0.190 AC: 7871 AN: 41512

American (AMR) AF: 0.361 AC: 5510 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.531 AC: 1843 AN: 3468

East Asian (EAS) AF: 0.108 AC: 560 AN: 5182

South Asian (SAS) AF: 0.326 AC: 1574 AN: 4828

European-Finnish (FIN) AF: 0.237 AC: 2505 AN: 10564

Middle Eastern (MID) AF: 0.473 AC: 139 AN: 294

European-Non Finnish (NFE) AF: 0.346 AC: 23499 AN: 67996

Other (OTH) AF: 0.320 AC: 675 AN: 2112

Alfa AF: 0.339 Hom.: 25083

Bravo AF: 0.295

Asia WGS AF: 0.239 AC: 832 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	0.074
DANN	Benign	0.33
PhyloP100		-2.9
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: rs42404; hg19: chr5-14417929;