chr1-54787747-G-A

Variant names:

• chr1-54787747-G-A
• rs144865731
• NM_001114108.2:c.703C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001114108.2(TTC22):​c.703C>T​(p.Arg235Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 1,613,444 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000088 (0 hom.)
• Consequence: TTC22 NM_001114108.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.26
• Publications: 3 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07523885).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTC22	NM_001114108.2	c.703C>T	p.Arg235Trp	missense_variant	Exon 3 of 7	ENST00000371276.9	NP_001107580.1
TTC22	NM_017904.4	c.703C>T	p.Arg235Trp	missense_variant	Exon 3 of 6		NP_060374.2
TTC22	XM_011541671.3	c.703C>T	p.Arg235Trp	missense_variant	Exon 3 of 6		XP_011539973.1
TTC22	XM_017001582.2	c.130C>T	p.Arg44Trp	missense_variant	Exon 3 of 7		XP_016857071.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTC22	ENST00000371276.9	c.703C>T	p.Arg235Trp	missense_variant	Exon 3 of 7	5	NM_001114108.2	ENSP00000360323.4

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000104 AC: 26 AN: 249468 AF XY: 0.000119

Gnomad AFR exome AF: 0.0000628

Gnomad AMR exome AF: 0.0000872

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000177

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.0000883 AC: 129 AN: 1461142 Hom.: 0 Cov.: 31 AF XY: 0.0000894 AC XY: 65 AN XY: 726782

African (AFR) AF: 0.0000897 AC: 3 AN: 33460

American (AMR) AF: 0.000269 AC: 12 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26082

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86070

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53344

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.0000873 AC: 97 AN: 1111738

Other (OTH) AF: 0.000182 AC: 11 AN: 60350

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19 AN XY: 74476

African (AFR) AF: 0.0000481 AC: 2 AN: 41576

American (AMR) AF: 0.00137 AC: 21 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68018

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.000416

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000123 AC: 15

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 03, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.703C>T (p.R235W) alteration is located in exon 3 (coding exon 3) of the TTC22 gene. This alteration results from a C to T substitution at nucleotide position 703, causing the arginine (R) at amino acid position 235 to be replaced by a tryptophan (W). 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	Benign	0.12
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T;.;.
Eigen	Benign	0.012
Eigen_PC	Benign	-0.012
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.075	T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.7	L;L;.
PhyloP100		2.3
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.1	D;D;D
REVEL	Benign	0.13
Sift	Uncertain	0.015	D;D;D
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		0.99	D;D;.
Vest4		0.50
MVP		0.32
MPC		0.68
ClinPred		0.22	T
GERP RS		3.5
PromoterAI		0.0058	Neutral
Varity_R		0.10
gMVP		0.45
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs144865731; hg19: chr1-55253420; COSMIC: COSV64881653;