20-37999220-C-T

Position:

• chr20-37999220-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_001303457.2(TTI1):​c.2761G>A​(p.Asp921Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTI1 NM_001303457.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.16

Genes affected

TTI1 (HGNC:29029): (TELO2 interacting protein 1) Involved in regulation of TOR signaling. Located in cytoplasm. Part of TORC1 complex and TORC2 complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-37999220-C-T is Pathogenic according to our data. Variant chr20-37999220-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 402171.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr20-37999220-C-T is described in Lovd as [Pathogenic]. Variant chr20-37999220-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTI1	NM_001303457.2	c.2761G>A	p.Asp921Asn	missense_variant	5/8	ENST00000373447.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTI1	ENST00000373447.8	c.2761G>A	p.Asp921Asn	missense_variant	5/8	1	NM_001303457.2	P1
TTI1	ENST00000373448.6	c.2761G>A	p.Asp921Asn	missense_variant	6/9	1		P1
TTI1	ENST00000449821.1	c.2761G>A	p.Asp921Asn	missense_variant	4/7	2		P1
TTI1	ENST00000473288.1	n.220G>A		non_coding_transcript_exon_variant	2/4	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1353006 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 670034

Gnomad4 AFR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Abnormal brain morphology Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

-

- -

Neurodevelopmental disorder with microcephaly and movement abnormalities Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 21, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.028	T;T;T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	.;.;D
M_CAP	Benign	0.072	D
MetaRNN	Uncertain	0.71	D;D;D
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.7	L;L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.18
Sift	Benign	0.041	D;D;D
Sift4G	Uncertain	0.044	D;D;D
Polyphen		0.90	P;P;P
Vest4		0.58
MutPred		0.43		Gain of MoRF binding (P = 0.0335);Gain of MoRF binding (P = 0.0335);Gain of MoRF binding (P = 0.0335);
MVP		0.55
MPC		0.59
ClinPred		0.90	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.14
gMVP		0.29

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: rs375131638; hg19: chr20-36627622;