rs121909075

chr6-35500100-A-Gchr6-35500100-A-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM5 BP4_Strong BP6

The NM_003322.6(TULP1):c.1376T>C(p.Ile459Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000265 in 1,614,178 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I459L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: TULP1 NM_003322.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 7.47

Genes affected

TULP1 (HGNC:12423): (TUB like protein 1) This gene encodes a member of the tubby-like gene family (TULPs). Members of this family have been identified in plants, vertebrates, and invertebrates. TULP proteins share a conserved C-terminal region of approximately 200 amino acid residues. The protein encoded by this gene is thought to play a role in the physiology of photoreceptors. Mutations in this gene are associated with recessive juvenile retinitis pigmentosa and Leber congenital amaurosis-15. [provided by RefSeq, Nov 2016]

LOC124901309 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-35500100-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7359.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.058392078).
• BP6: Variant 6-35500100-A-G is Benign according to our data. Variant chr6-35500100-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 194380.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TULP1	NM_003322.6	c.1376T>C	p.Ile459Thr	missense_variant	14/15	ENST00000229771.11
LOC124901309	XR_007059561.1	n.75+1893A>G		intron_variant, non_coding_transcript_variant
TULP1	NM_001289395.2	c.1217T>C	p.Ile406Thr	missense_variant	13/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TULP1	ENST00000229771.11	c.1376T>C	p.Ile459Thr	missense_variant	14/15	1	NM_003322.6	P4
TULP1	ENST00000322263.8	c.1217T>C	p.Ile406Thr	missense_variant	13/14	1		A2
TULP1	ENST00000614066.4	c.1370T>C	p.Ile457Thr	missense_variant	13/14	5		A2
TULP1	ENST00000495781.1	n.552T>C		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes AF: 0.00127 AC: 193 AN: 152184 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000429 AC: 108 AN: 251456 Hom.: 0 AF XY: 0.000405 AC XY: 55 AN XY: 135908

Gnomad AFR exome AF: 0.00388

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000161 AC: 235 AN: 1461876 Hom.: 1 Cov.: 32 AF XY: 0.000149 AC XY: 108 AN XY: 727240

Gnomad4 AFR exome AF: 0.00293

Gnomad4 AMR exome AF: 0.000961

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000629

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.00126 AC: 192 AN: 152302 Hom.: 1 Cov.: 32 AF XY: 0.00122 AC XY: 91 AN XY: 74468

Gnomad4 AFR AF: 0.00431

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000597 Hom.: 0

Bravo AF: 0.00126

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000486 AC: 59

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 24, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29843741, 27440997, 24154662, 32037395) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 04, 2014	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 30, 2023

Variant summary: TULP1 c.1376T>C (p.Ile459Thr) results in a non-conservative amino acid change located in the Tubby, C-terminal domain (IPR000007) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00043 in 251456 control chromosomes, predominantly at a frequency of 0.0039 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 8 fold of the estimated maximal expected allele frequency for a pathogenic variant in TULP1 causing Leber Congenital Amaurosis phenotype (0.0005), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin.c.1376T>C has been reported in the literature in individuals affected with Retinitis Pigmentosa (e.g. Wang_2014, Zampaglione_2020). These reports do not provide unequivocal conclusions about association of the variant with Leber Congenital Amaurosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24154662, 32037395). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely benign, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -

TULP1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 05, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.39
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D;D;D
MetaRNN	Benign	0.058	T;T;T
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-4.4	D;D;.
REVEL	Pathogenic	0.86
Sift	Benign	0.098	T;T;.
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		0.76	P;P;.
Vest4		0.85
MVP		0.93
MPC		0.93
ClinPred		0.047	T
GERP RS		5.3
Varity_R		0.64
gMVP		0.60

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

Publications

LitVar

Other links and lift over

dbSNP: rs121909075; hg19: chr6-35467877; COSMIC: COSV100003766; COSMIC: COSV100003766;