NM_024753.5:c.703G>C

Variant names:

• chr2-165941034-C-G
• rs150742619
• NM_024753.5:c.703G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_024753.5(TTC21B):​c.703G>C​(p.Ala235Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,613,670 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 (★★). Synonymous variant affecting the same amino acid position (i.e. A235A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TTC21B NM_024753.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:2 U:4
• Conservation: PhyloP100: 6.11
• Publications: 0 publications found

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]

TTC21B-AS1 (HGNC:41115): (TTC21B antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.805

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024753.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC21B	NM_024753.5	MANE Select	c.703G>C	p.Ala235Pro	missense	Exon 6 of 29	NP_079029.3
	TTC21B-AS1	NR_038983.1		n.277-6163C>G		intron	N/A
	TTC21B-AS1	NR_038984.1		n.221-6163C>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC21B	ENST00000243344.8	TSL:1 MANE Select	c.703G>C	p.Ala235Pro	missense	Exon 6 of 29	ENSP00000243344.7
	TTC21B	ENST00000464374.5	TSL:1	n.743G>C		non_coding_transcript_exon	Exon 6 of 11
	TTC21B	ENST00000679840.1		c.703G>C	p.Ala235Pro	missense	Exon 6 of 27	ENSP00000505248.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152176 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461494 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727040

African (AFR) AF: 0.0000598 AC: 2 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111720

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152176 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74352

African (AFR) AF: 0.000193 AC: 8 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000491

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Jeune thoracic dystrophy (2)
-	1	-	Asphyxiating thoracic dystrophy 4;C3151186:Nephronophthisis 12 (1)
-	1	-	Jeune thoracic dystrophy;C0687120:Nephronophthisis (1)
-	1	-	not provided (1)
-	1	-	TTC21B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.058	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.33	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		6.1
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.054	T
Polyphen		0.96	D
Vest4		0.89
MVP		0.35
MPC		0.23
ClinPred		0.98	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.72
gMVP		0.84
Mutation Taster		=29/71	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: rs150742619; hg19: chr2-166797544;