chr14-20292103-A-C

Variant names:

• chr14-20292103-A-C
• rs1037825217
• NM_138376.3:c.1083T>G

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.1083T>G​(p.Asp361Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000114 in 1,581,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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: 0.000012 (0 hom.)
• Consequence: TTC5 NM_138376.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.84
• Publications: 1 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=0.032307565).

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.1083T>G	p.Asp361Glu	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.1083T>G	p.Asp361Glu	missense	Exon 9 of 10	ENSP00000258821.3	Q8N0Z6
	TTC5	ENST00000383029.7	TSL:1	n.*628T>G		non_coding_transcript_exon	Exon 9 of 10	ENSP00000372496.3	H9KV81
	TTC5	ENST00000383029.7	TSL:1	n.*628T>G		3_prime_UTR	Exon 9 of 10	ENSP00000372496.3	H9KV81

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000119 AC: 17 AN: 1429160 Hom.: 0 Cov.: 31 AF XY: 0.0000141 AC XY: 10 AN XY: 711504

African (AFR) AF: 0.00 AC: 0 AN: 32494

American (AMR) AF: 0.00 AC: 0 AN: 40776

Ashkenazi Jewish (ASJ) AF: 0.000276 AC: 7 AN: 25364

East Asian (EAS) AF: 0.00 AC: 0 AN: 38148

South Asian (SAS) AF: 0.00 AC: 0 AN: 80896

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51916

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5630

European-Non Finnish (NFE) AF: 0.00000913 AC: 10 AN: 1095408

Other (OTH) AF: 0.00 AC: 0 AN: 58528

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152126 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74300

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

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	0.077
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	14
DANN	Benign	0.29
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.032	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.5	N
PhyloP100		1.8
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	0.72	N
REVEL	Benign	0.13
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.11
MutPred		0.39		Loss of catalytic residue at C364 (P = 0.1573)
MVP		0.17
MPC		0.15
ClinPred		0.033	T
GERP RS		-3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.26
Mutation Taster		=81/19	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: rs1037825217; hg19: chr14-20760262;