rs1251881716

Variant names:

• chr1-54787064-A-G
• rs1251881716
• NM_001114108.2:c.751T>C

Your query was ambiguous. Multiple possible variants found:

• chr1-54787064-A-G
• chr1-54787064-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001114108.2(TTC22):​c.751T>C​(p.Cys251Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000197 in 1,525,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: TTC22 NM_001114108.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.12
• Publications: 0 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.863

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTC22	NM_001114108.2	c.751T>C	p.Cys251Arg	missense_variant	Exon 4 of 7	ENST00000371276.9	NP_001107580.1
TTC22	NM_017904.4	c.751T>C	p.Cys251Arg	missense_variant	Exon 4 of 6		NP_060374.2
TTC22	XM_011541671.3	c.751T>C	p.Cys251Arg	missense_variant	Exon 4 of 6		XP_011539973.1
TTC22	XM_017001582.2	c.178T>C	p.Cys60Arg	missense_variant	Exon 4 of 7		XP_016857071.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTC22	ENST00000371276.9	c.751T>C	p.Cys251Arg	missense_variant	Exon 4 of 7	5	NM_001114108.2	ENSP00000360323.4

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151814 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: 0.00000146 AC: 2 AN: 1373794 Hom.: 0 Cov.: 29 AF XY: 0.00000296 AC XY: 2 AN XY: 675722

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

African (AFR) AF: 0.00 AC: 0 AN: 31334

American (AMR) AF: 0.00 AC: 0 AN: 32554

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23022

East Asian (EAS) AF: 0.00 AC: 0 AN: 35918

South Asian (SAS) AF: 0.00 AC: 0 AN: 74554

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48672

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5002

European-Non Finnish (NFE) AF: 0.00000188 AC: 2 AN: 1065794

Other (OTH) AF: 0.00 AC: 0 AN: 56944

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151814 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74148

African (AFR) AF: 0.00 AC: 0 AN: 41294

American (AMR) AF: 0.00 AC: 0 AN: 15250

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5130

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

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: 0.0000147 AC: 1 AN: 67948

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.751T>C (p.C251R) alteration is located in exon 4 (coding exon 4) of the TTC22 gene. This alteration results from a T to C substitution at nucleotide position 751, causing the cysteine (C) at amino acid position 251 to be replaced by an arginine (R). 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	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T;.;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.74	T;T;T
M_CAP	Benign	0.032	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.3	M;M;.
PhyloP100		8.1
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-6.1	D;D;D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.97
MutPred		0.60		Gain of MoRF binding (P = 0.0036);Gain of MoRF binding (P = 0.0036);.;
MVP		0.57
MPC		1.3
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.92
gMVP		0.85
Mutation Taster		=33/67	disease causing

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: rs1251881716; hg19: chr1-55252737;