rs141980901
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1PM2BP4_StrongBP6
The NM_003322.6(TULP1):c.1486G>A(p.Ala496Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000712 in 1,614,038 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict 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. A496V) has been classified as Uncertain significance.
Frequency
Consequence
NM_003322.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TULP1 | NM_003322.6 | c.1486G>A | p.Ala496Thr | missense_variant | 14/15 | ENST00000229771.11 | |
LOC124901309 | XR_007059561.1 | n.75+1783C>T | intron_variant, non_coding_transcript_variant | ||||
TULP1 | NM_001289395.2 | c.1327G>A | p.Ala443Thr | missense_variant | 13/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TULP1 | ENST00000229771.11 | c.1486G>A | p.Ala496Thr | missense_variant | 14/15 | 1 | NM_003322.6 | P4 | |
TULP1 | ENST00000322263.8 | c.1327G>A | p.Ala443Thr | missense_variant | 13/14 | 1 | A2 | ||
TULP1 | ENST00000614066.4 | c.1480G>A | p.Ala494Thr | missense_variant | 13/14 | 5 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.00108 AC: 164AN: 152148Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.000860 AC: 216AN: 251230Hom.: 0 AF XY: 0.000861 AC XY: 117AN XY: 135822
GnomAD4 exome AF: 0.000674 AC: 985AN: 1461772Hom.: 0 Cov.: 32 AF XY: 0.000649 AC XY: 472AN XY: 727204
GnomAD4 genome ? AF: 0.00108 AC: 164AN: 152266Hom.: 1 Cov.: 32 AF XY: 0.00121 AC XY: 90AN XY: 74450
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:3Other:1
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
not provided, no classification provided | literature only | Retina International | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | - - |
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 24, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 03, 2022 | Variant summary: TULP1 c.1486G>A (p.Ala496Thr) 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 benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00086 in 251230 control chromosomes, predominantly at a frequency of 0.0027 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 5.4 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 Latino origin. c.1486G>A has been reported in the literature as a heterozygous variant in at-least one in individual affected with Leber Congenital Amaurosis, who had an alternate molecular basis of disease described below (example, El Shamieh_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Leber Congenital Amaurosis. The co-occurrence with another reported pathogenic RP1 gene variant is, homozygous c.2391_2392delAA, p.Asp799*, in the proband from a consanguineous family, providing supporting evidence for a benign role (El Shamieh_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2; VUS, n=2). Based on the evidence outlined above, the variant was classified as benign. - |
Leber congenital amaurosis 15 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Retinitis pigmentosa Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at