rs1294549037

Positions:

• chr2-165880771-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_024753.5(TTC21B):​c.3713G>A​(p.Gly1238Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,576 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TTC21B NM_024753.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.71

Genes affected

TTC21B (HGNC:25660): (tetratricopeptide repeat domain 21B) This gene encodes a member of TTC21 family, containing several tetratricopeptide repeat (TPR) domains. This protein is localized to the cilium axoneme, and may play a role in retrograde intraflagellar transport in cilia. Mutations in this gene are associated with various ciliopathies, nephronophthisis 12, and asphyxiating thoracic dystrophy 4. [provided by RefSeq, Oct 2011]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTC21B	NM_024753.5	c.3713G>A	p.Gly1238Glu	missense_variant	27/29	ENST00000243344.8	NP_079029.3
TTC21B	XM_017004967.2	c.3713G>A	p.Gly1238Glu	missense_variant	27/28		XP_016860456.1
TTC21B	XM_047445870.1	c.3059G>A	p.Gly1020Glu	missense_variant	23/25		XP_047301826.1
TTC21B	XM_011511871.4	c.2963G>A	p.Gly988Glu	missense_variant	22/24		XP_011510173.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTC21B	ENST00000243344.8	c.3713G>A	p.Gly1238Glu	missense_variant	27/29	1	NM_024753.5	ENSP00000243344	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460576 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726636

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Asphyxiating thoracic dystrophy 4;C3151186:Nephronophthisis 12 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 17, 2022

- -

Nephronophthisis 12 Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Jun 26, 2017

This missense variant G1238E is absent from gnomAD and is found in trans to a pathogenic variant (P209L) and is predicted to be damaging. (PM2, PM3, PP3) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.071	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Pathogenic	3.5	H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-7.1	D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.83		Gain of ubiquitination at K1243 (P = 0.0619);
MVP		0.55
MPC		0.25
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.84

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

Publications

LitVar

Other links and lift over

dbSNP: rs1294549037; hg19: chr2-166737281;