NM_138376.3:c.1177C>T

Variant names:

• chr14-20292009-G-A
• rs1881963746
• NM_138376.3:c.1177C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_138376.3(TTC5):​c.1177C>T​(p.Leu393Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000126 in 1,590,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: TTC5 NM_138376.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.43
• Publications: 0 publications found

Genes affected

TTC5 (HGNC:19274): (tetratricopeptide repeat domain 5) Predicted to enable DNA binding activity and chromatin binding activity. Predicted to be involved in DNA repair. Predicted to act upstream of or within positive regulation of transcription by RNA polymerase II. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

TTC5 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with cerebral atrophy and variable facial dysmorphism

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.060672194).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138376.3. 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
	TTC5	NM_138376.3	MANE Select	c.1177C>T	p.Leu393Phe	missense	Exon 9 of 10	NP_612385.2	Q8N0Z6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC5	ENST00000258821.8	TSL:1 MANE Select	c.1177C>T	p.Leu393Phe	missense	Exon 9 of 10	ENSP00000258821.3	Q8N0Z6
	TTC5	ENST00000383029.7	TSL:1	n.*722C>T		non_coding_transcript_exon	Exon 9 of 10	ENSP00000372496.3	H9KV81
	TTC5	ENST00000383029.7	TSL:1	n.*722C>T		3_prime_UTR	Exon 9 of 10	ENSP00000372496.3	H9KV81

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.95e-7 AC: 1 AN: 1438810 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 716110

African (AFR) AF: 0.00 AC: 0 AN: 32648

American (AMR) AF: 0.00 AC: 0 AN: 41194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25552

East Asian (EAS) AF: 0.00 AC: 0 AN: 38574

South Asian (SAS) AF: 0.00 AC: 0 AN: 82518

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52558

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5672

European-Non Finnish (NFE) AF: 9.08e-7 AC: 1 AN: 1100978

Other (OTH) AF: 0.00 AC: 0 AN: 59116

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74332

African (AFR) AF: 0.00 AC: 0 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5206

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	13
DANN	Benign	0.81
DEOGEN2	Benign	0.019	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N
PhyloP100		2.4
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.018
Sift	Benign	0.12	T
Sift4G	Benign	0.086	T
Polyphen		0.073	B
Vest4		0.13
MutPred		0.30		Gain of helix (P = 0.0199)
MVP		0.20
MPC		0.18
ClinPred		0.40	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.16
Mutation Taster		=75/25	polymorphism

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: rs1881963746; hg19: chr14-20760168;