1-54787064-A-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001114108.2(TTC22):​c.751T>A​(p.Cys251Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000728 in 1,373,794 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C251R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: TTC22 NM_001114108.2 missense
• Clinical Significance: Not reported in ClinVar
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTC22	NM_001114108.2	c.751T>A	p.Cys251Ser	missense_variant	Exon 4 of 7	ENST00000371276.9	NP_001107580.1
TTC22	NM_017904.4	c.751T>A	p.Cys251Ser	missense_variant	Exon 4 of 6		NP_060374.2
TTC22	XM_011541671.3	c.751T>A	p.Cys251Ser	missense_variant	Exon 4 of 6		XP_011539973.1
TTC22	XM_017001582.2	c.178T>A	p.Cys60Ser	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>A	p.Cys251Ser	missense_variant	Exon 4 of 7	5	NM_001114108.2	ENSP00000360323.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.28e-7 AC: 1 AN: 1373794 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 675722

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: 9.38e-7 AC: 1 AN: 1065794

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

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T;.;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.76	T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.72	D;D;D
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.3	M;M;.
PhyloP100		8.1
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-4.2	D;D;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.021	D;D;D
Sift4G	Uncertain	0.029	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.90
MutPred		0.59		Loss of stability (P = 0.04);Loss of stability (P = 0.04);.;
MVP		0.42
MPC		0.68
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.53
gMVP		0.57
Mutation Taster		=40/60	disease causing

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: rs1251881716; hg19: chr1-55252737;