5-14143769-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2 BP4_Moderate BP6 BS1 BS2

The NM_007118.4(TRIO):c.44C>T(p.Ser15Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000915 in 1,005,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: TRIO NM_007118.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 2.26

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TRIO
• BP4: Computational evidence support a benign effect (MetaRNN=0.21686533).
• BP6: Variant 5-14143769-C-T is Benign according to our data. Variant chr5-14143769-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1242140.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00041 (60/146342) while in subpopulation AFR AF= 0.00135 (55/40820). AF 95% confidence interval is 0.00106. There are 0 homozygotes in gnomad4. There are 29 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 60 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIO	NM_007118.4	c.44C>T	p.Ser15Phe	missense_variant	1/57	ENST00000344204.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIO	ENST00000344204.9	c.44C>T	p.Ser15Phe	missense_variant	1/57	1	NM_007118.4	P1
TRIO	ENST00000698541.1	c.44C>T	p.Ser15Phe	missense_variant	1/37
TRIO	ENST00000502816.1	n.68C>T		non_coding_transcript_exon_variant	1/5	2
TRIO	ENST00000505971.5	n.68C>T		non_coding_transcript_exon_variant	1/4	3

Frequencies

GnomAD3 genomes AF: 0.000410 AC: 60 AN: 146342 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000136

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000152

Gnomad OTH AF: 0.000988

GnomAD4 exome AF: 0.0000373 AC: 32 AN: 858746 Hom.: 0 Cov.: 29 AF XY: 0.0000251 AC XY: 10 AN XY: 398954

Gnomad4 AFR exome AF: 0.00153

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: 0.00000257

Gnomad4 OTH exome AF: 0.000104

GnomAD4 genome AF: 0.000410 AC: 60 AN: 146342 Hom.: 0 Cov.: 31 AF XY: 0.000408 AC XY: 29 AN XY: 71150

Gnomad4 AFR AF: 0.00135

Gnomad4 AMR AF: 0.000136

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000152

Gnomad4 OTH AF: 0.000988

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000404

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 28, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 20, 2020	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 01, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.31
Cadd	Uncertain	23
Dann	Benign	0.97
DEOGEN2	Benign	0.049	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.44	T
M_CAP	Pathogenic	0.91	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	0.96	N;N
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.68	P
Vest4		0.25
MVP		0.19
MPC		0.91
ClinPred		0.36	T
GERP RS		1.3
Varity_R		0.16
gMVP		0.20

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

Publications

LitVar

Other links and lift over

dbSNP: rs1006366530; hg19: chr5-14143878; COSMIC: COSV60094513; COSMIC: COSV60094513;