rs1133834

Variant names:

• chr14-75902201-T-C
• rs1133834
• NM_015072.5:c.3800T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015072.5(TTLL5):​c.3800T>C​(p.Phe1267Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 1,613,720 control chromosomes in the GnomAD database, including 50,283 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (9156 hom., cov: 32)
  • Exomes 𝑓: 0.22 (41127 hom.)
• Consequence: TTLL5 NM_015072.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.386
• Publications: 28 publications found

Genes affected

TTLL5 (HGNC:19963): (tubulin tyrosine ligase like 5) This gene encodes a member of the tubulin tyrosine ligase like protein family. This protein interacts with two glucocorticoid receptor coactivators, transcriptional intermediary factor 2 and steroid receptor coactivator 1. This protein may function as a coregulator of glucocorticoid receptor mediated gene induction and repression. This protein may also function as an alpha tubulin polyglutamylase.[provided by RefSeq, Feb 2010]

IFT43 (HGNC:29669): (intraflagellar transport 43) This gene encodes a subunit of the intraflagellar transport complex A (IFT-A). IFT-A is a multiprotein complex that plays an important role in cilia assembly and maintenance by mediating retrograde ciliary transport. Mutations in this gene are a cause of cranioectodermal dysplasia-3 (CED3), also known as Sensenbrenner syndrome. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

IFT43 Gene-Disease associations (from GenCC):

• cranioectodermal dysplasia 3

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• short-rib thoracic dysplasia 18 with polydactyly

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• cranioectodermal dysplasia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• ciliopathy

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• retinitis pigmentosa 81

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.6160398E-5).
• BP6: Variant 14-75902201-T-C is Benign according to our data. Variant chr14-75902201-T-C is described in ClinVar as Benign. ClinVar VariationId is 677213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.512 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015072.5. 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
	TTLL5	NM_015072.5	MANE Select	c.3800T>C	p.Phe1267Ser	missense	Exon 31 of 32	NP_055887.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTLL5	ENST00000298832.14	TSL:1 MANE Select	c.3800T>C	p.Phe1267Ser	missense	Exon 31 of 32	ENSP00000298832.9	Q6EMB2-1
	TTLL5	ENST00000882579.1		c.3803T>C	p.Phe1268Ser	missense	Exon 31 of 32	ENSP00000552638.1
	TTLL5	ENST00000882582.1		c.3803T>C	p.Phe1268Ser	missense	Exon 31 of 32	ENSP00000552641.1

Frequencies

GnomAD3 genomes AF: 0.309 AC: 46873 AN: 151924 Hom.: 9126 Cov.: 32

Gnomad AFR AF: 0.517

Gnomad AMI AF: 0.424

Gnomad AMR AF: 0.356

Gnomad ASJ AF: 0.233

Gnomad EAS AF: 0.511

Gnomad SAS AF: 0.411

Gnomad FIN AF: 0.143

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.176

Gnomad OTH AF: 0.307

GnomAD2 exomes AF: 0.282 AC: 70728 AN: 250988 AF XY: 0.278

Gnomad AFR exome AF: 0.521

Gnomad AMR exome AF: 0.384

Gnomad ASJ exome AF: 0.229

Gnomad EAS exome AF: 0.532

Gnomad FIN exome AF: 0.142

Gnomad NFE exome AF: 0.179

Gnomad OTH exome AF: 0.256

GnomAD4 exome AF: 0.215 AC: 314666 AN: 1461678 Hom.: 41127 Cov.: 33 AF XY: 0.219 AC XY: 159376 AN XY: 727154

African (AFR) AF: 0.537 AC: 17982 AN: 33472

American (AMR) AF: 0.381 AC: 17033 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.235 AC: 6148 AN: 26132

East Asian (EAS) AF: 0.503 AC: 19953 AN: 39694

South Asian (SAS) AF: 0.391 AC: 33680 AN: 86248

European-Finnish (FIN) AF: 0.144 AC: 7701 AN: 53392

Middle Eastern (MID) AF: 0.317 AC: 1827 AN: 5766

European-Non Finnish (NFE) AF: 0.175 AC: 195022 AN: 1111878

Other (OTH) AF: 0.254 AC: 15320 AN: 60390

GnomAD4 genome AF: 0.309 AC: 46964 AN: 152042 Hom.: 9156 Cov.: 32 AF XY: 0.311 AC XY: 23085 AN XY: 74340

African (AFR) AF: 0.518 AC: 21441 AN: 41428

American (AMR) AF: 0.356 AC: 5445 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 808 AN: 3468

East Asian (EAS) AF: 0.511 AC: 2636 AN: 5156

South Asian (SAS) AF: 0.411 AC: 1981 AN: 4822

European-Finnish (FIN) AF: 0.143 AC: 1517 AN: 10602

Middle Eastern (MID) AF: 0.361 AC: 106 AN: 294

European-Non Finnish (NFE) AF: 0.176 AC: 11991 AN: 67984

Other (OTH) AF: 0.312 AC: 655 AN: 2102

Alfa AF: 0.226 Hom.: 20855

Bravo AF: 0.337

TwinsUK AF: 0.167 AC: 619

ALSPAC AF: 0.172 AC: 662

ESP6500AA AF: 0.508 AC: 2238

ESP6500EA AF: 0.179 AC: 1537

ExAC AF: 0.283 AC: 34356

Asia WGS AF: 0.516 AC: 1797 AN: 3478

EpiCase AF: 0.196

EpiControl AF: 0.194

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	18
DANN	Benign	0.79
DEOGEN2	Benign	0.012	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.000026	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.57	N
PhyloP100		0.39
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.49	N
REVEL	Benign	0.063
Sift	Benign	0.37	T
Sift4G	Benign	0.45	T
Polyphen		0.0	B
Vest4		0.098
MPC		0.16
ClinPred		0.0023	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.046
gMVP		0.28
Mutation Taster		=97/3	polymorphism (auto)

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: rs1133834; hg19: chr14-76368544; COSMIC: COSV54036156;