6-35503816-A-T

Variant names:

• chr6-35503816-A-T
• rs121909076
• NM_003322.6:c.1145T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP2

The NM_003322.6(TULP1):​c.1145T>A​(p.Phe382Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F382S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TULP1 NM_003322.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.18
• Publications: 0 publications found

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]

TULP1 Gene-Disease associations (from GenCC):

• retinitis pigmentosa 14

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Leber congenital amaurosis 15

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Leber congenital amaurosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LINC03135 (HGNC:58100):

LOC124901309 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_003322.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-35503816-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 7362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 30 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: 0.64726 (below the threshold of 3.09). Trascript score misZ: -0.4024 (below the threshold of 3.09). GenCC associations: The gene is linked to retinitis pigmentosa, retinitis pigmentosa 14, Leber congenital amaurosis, Leber congenital amaurosis 15.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003322.6. 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
	TULP1	NM_003322.6	MANE Select	c.1145T>A	p.Phe382Tyr	missense	Exon 12 of 15	NP_003313.3
	TULP1	NM_001289395.2		c.986T>A	p.Phe329Tyr	missense	Exon 11 of 14	NP_001276324.1	O00294-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TULP1	ENST00000229771.11	TSL:1 MANE Select	c.1145T>A	p.Phe382Tyr	missense	Exon 12 of 15	ENSP00000229771.6	O00294-1
	TULP1	ENST00000322263.8	TSL:1	c.986T>A	p.Phe329Tyr	missense	Exon 11 of 14	ENSP00000319414.4	O00294-2
	TULP1	ENST00000614066.4	TSL:5	c.1139T>A	p.Phe380Tyr	missense	Exon 11 of 14	ENSP00000477534.1	A0A087WT25

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.14
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.73	T
M_CAP	Uncertain	0.093	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	-0.12	N
PhyloP100		4.2
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	0.71	N
REVEL	Uncertain	0.55
Sift	Benign	0.87	T
Sift4G	Benign	0.78	T
Polyphen		0.13	B
Vest4		0.34
MutPred		0.84		Gain of phosphorylation at F382 (P = 0.0698)
MVP		0.52
MPC		0.47
ClinPred		0.86	D
GERP RS		5.0
Varity_R		0.42
gMVP		0.58
Mutation Taster		=65/35	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121909076; hg19: chr6-35471593;