20-37999220-C-G

Variant names:

• chr20-37999220-C-G
• NM_001303457.2:c.2761G>C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_001303457.2(TTI1):​c.2761G>C​(p.Asp921His) variant causes a missense change. The variant allele was found at a frequency of 0.000000739 in 1,353,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D921N) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: TTI1 NM_001303457.2 missense
• Clinical Significance: Not reported in ClinVar
• 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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr20-37999220-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.814

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTI1	NM_001303457.2	c.2761G>C	p.Asp921His	missense_variant	Exon 5 of 8	ENST00000373447.8	NP_001290386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTI1	ENST00000373447.8	c.2761G>C	p.Asp921His	missense_variant	Exon 5 of 8	1	NM_001303457.2	ENSP00000362546.3
TTI1	ENST00000373448.6	c.2761G>C	p.Asp921His	missense_variant	Exon 6 of 9	1		ENSP00000362547.2
TTI1	ENST00000449821.1	c.2761G>C	p.Asp921His	missense_variant	Exon 4 of 7	2		ENSP00000407270.1
TTI1	ENST00000473288.1	n.220G>C		non_coding_transcript_exon_variant	Exon 2 of 4	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.39e-7 AC: 1 AN: 1353006 Hom.: 0 Cov.: 30 AF XY: 0.00000149 AC XY: 1 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: 9.46e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T;T;T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	.;.;D
M_CAP	Benign	0.077	D
MetaRNN	Pathogenic	0.81	D;D;D
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Uncertain	2.4	M;M;M
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.5	D;D;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.010	D;D;D
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.78
MutPred		0.45		Gain of MoRF binding (P = 0.0459);Gain of MoRF binding (P = 0.0459);Gain of MoRF binding (P = 0.0459);
MVP		0.80
MPC		0.67
ClinPred		0.96	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.34
gMVP		0.49

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-36627622;