Genetic Variant NM_001114108.2:c.1651A>G (chr1-54781302-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001114108.2(TTC22):c.1651A>G(p.Met551Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000151 in 1,320,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

TTC22
NM_001114108.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.394

Publications

0 publications found

Variant links:

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]

TTC22 links:

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ACMG classification

Classification was made for transcript

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=0.05350703).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTC22	NM_001114108.2 link	c.1651A>G	p.Met551Val	missense_variant	Exon 7 of 7	ENST00000371276.9	NP_001107580.1	Q5TAA0-1
TTC22	XM_011541671.3 link	c.1498A>G	p.Met500Val	missense_variant	Exon 6 of 6		XP_011539973.1
TTC22	XM_017001582.2 link	c.1078A>G	p.Met360Val	missense_variant	Exon 7 of 7		XP_016857071.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTC22	ENST00000371276.9 link	c.1651A>G	p.Met551Val	missense_variant	Exon 7 of 7	5	NM_001114108.2	ENSP00000360323.4		Q5TAA0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000151

AC:

AN:

1320986

Hom.:

Cov.:

AF XY:

0.00000154

AC XY:

AN XY:

651152

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

26322

American (AMR)

AF:

0.00

AC:

AN:

25202

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22898

East Asian (EAS)

AF:

0.00

AC:

AN:

28702

South Asian (SAS)

AF:

0.00

AC:

AN:

72912

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33020

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4554

European-Non Finnish (NFE)

AF:

0.00000190

AC:

AN:

1052634

Other (OTH)

AF:

0.00

AC:

AN:

54742

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.250

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 09, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1651A>G (p.M551V) alteration is located in exon 7 (coding exon 7) of the TTC22 gene. This alteration results from a A to G substitution at nucleotide position 1651, causing the methionine (M) at amino acid position 551 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

Benign

0.11

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Benign

0.70

DEOGEN2

Benign

0.0034

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.57

M_CAP

Benign

0.0053

MetaRNN

Benign

0.054

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

PhyloP100

0.39

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.060

REVEL

Benign

0.068

Sift

Benign

1.0

Sift4G

Benign

0.76

Polyphen

0.020

Vest4

0.097

MutPred

0.18

Loss of MoRF binding (P = 0.1555);

MVP

0.20

MPC

0.29

ClinPred

0.050

GERP RS

3.9

Varity_R

0.16

gMVP

0.38

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over