NM_001114108.2:c.1001C>T

Variant names:

• chr1-54786002-G-A
• rs768907883
• NM_001114108.2:c.1001C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001114108.2(TTC22):​c.1001C>T​(p.Ala334Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000676 in 1,612,440 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000069 (0 hom.)
• Consequence: TTC22 NM_001114108.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.72
• Publications: 2 publications found

Genes affected

TTC22 (HGNC:26067): (tetratricopeptide repeat domain 22) This gene encodes a protein with seven tetratricopeptide (TPR) repeats. Tetratricopeptide repeat containing motifs are found in a variety of proteins and may mediate protein-protein interactions and chaperone activity. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jun 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37293625).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTC22	NM_001114108.2	c.1001C>T	p.Ala334Val	missense_variant	Exon 5 of 7	ENST00000371276.9	NP_001107580.1
TTC22	NM_017904.4	c.1001C>T	p.Ala334Val	missense_variant	Exon 5 of 6		NP_060374.2
TTC22	XM_011541671.3	c.1001C>T	p.Ala334Val	missense_variant	Exon 5 of 6		XP_011539973.1
TTC22	XM_017001582.2	c.428C>T	p.Ala143Val	missense_variant	Exon 5 of 7		XP_016857071.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTC22	ENST00000371276.9	c.1001C>T	p.Ala334Val	missense_variant	Exon 5 of 7	5	NM_001114108.2	ENSP00000360323.4
TTC22	ENST00000371274.8	c.1001C>T	p.Ala334Val	missense_variant	Exon 5 of 6	2		ENSP00000360321.4
TTC22	ENST00000448308.2	c.344C>T	p.Ala115Val	missense_variant	Exon 3 of 4	3		ENSP00000390300.2
TTC22	ENST00000488771.1	n.1994C>T		non_coding_transcript_exon_variant	Exon 1 of 3	2

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152122 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000404 AC: 10 AN: 247648 AF XY: 0.0000297

Gnomad AFR exome AF: 0.0000644

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000448

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000692 AC: 101 AN: 1460318 Hom.: 0 Cov.: 29 AF XY: 0.0000633 AC XY: 46 AN XY: 726448

African (AFR) AF: 0.0000598 AC: 2 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39660

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.0000828 AC: 92 AN: 1111702

Other (OTH) AF: 0.0000498 AC: 3 AN: 60220

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152122 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74318

African (AFR) AF: 0.0000966 AC: 4 AN: 41414

American (AMR) AF: 0.00 AC: 0 AN: 15270

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000901 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000577 AC: 7

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 14, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1001C>T (p.A334V) alteration is located in exon 5 (coding exon 5) of the TTC22 gene. This alteration results from a C to T substitution at nucleotide position 1001, causing the alanine (A) at amino acid position 334 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.14	T;.;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.37	T;T;T
MetaSVM	Uncertain	0.079	D
MutationAssessor	Uncertain	2.2	M;M;.
PhyloP100		8.7
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.6	D;D;D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0050	D;D;D
Sift4G	Uncertain	0.010	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.87
MutPred		0.25		Gain of MoRF binding (P = 0.1357);Gain of MoRF binding (P = 0.1357);.;
MVP		0.76
MPC		0.93
ClinPred		0.60	D
GERP RS		4.2
Varity_R		0.47
gMVP		0.71
Mutation Taster		=67/33	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs768907883; hg19: chr1-55251675; COSMIC: COSV64881198;