6-35498059-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003322.6(TULP1):c.*268C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0135 in 594,542 control chromosomes in the GnomAD database, including 327 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.034 (250 hom., cov: 32)
  • Exomes 𝑓: 0.0064 (77 hom.)
• Consequence: TULP1 NM_003322.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.510

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 6-35498059-G-T is Benign according to our data. Variant chr6-35498059-G-T is described in ClinVar as [Benign]. Clinvar id is 356464.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TULP1	NM_003322.6	c.*268C>A		3_prime_UTR_variant	15/15	ENST00000229771.11
TULP1	NM_001289395.2	c.*268C>A		3_prime_UTR_variant	14/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TULP1	ENST00000229771.11	c.*268C>A		3_prime_UTR_variant	15/15	1	NM_003322.6	P4
TULP1	ENST00000322263.8	c.*268C>A		3_prime_UTR_variant	14/14	1		A2
TULP1	ENST00000614066.4	c.*268C>A		3_prime_UTR_variant	14/14	5		A2

Frequencies

GnomAD3 genomes AF: 0.0341 AC: 5192 AN: 152200 Hom.: 248 Cov.: 32

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0162

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00227

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00284

Gnomad OTH AF: 0.0277

GnomAD4 exome AF: 0.00642 AC: 2840 AN: 442224 Hom.: 77 Cov.: 4 AF XY: 0.00575 AC XY: 1333 AN XY: 232008

Gnomad4 AFR exome AF: 0.113

Gnomad4 AMR exome AF: 0.0128

Gnomad4 ASJ exome AF: 0.00382

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00146

Gnomad4 FIN exome AF: 0.000633

Gnomad4 NFE exome AF: 0.00287

Gnomad4 OTH exome AF: 0.0118

GnomAD4 genome AF: 0.0342 AC: 5207 AN: 152318 Hom.: 250 Cov.: 32 AF XY: 0.0331 AC XY: 2469 AN XY: 74500

Gnomad4 AFR AF: 0.112

Gnomad4 AMR AF: 0.0161

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00282

Gnomad4 OTH AF: 0.0274

Alfa AF: 0.0184 Hom.: 25

Bravo AF: 0.0392

Asia WGS AF: 0.00837 AC: 30 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Leber congenital amaurosis 15 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Retinitis pigmentosa Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	9.3
Dann	Benign	0.68

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: rs114707578; hg19: chr6-35465836; COSMIC: COSV57693994; COSMIC: COSV57693994;