NM_003322.6:c.1102G>C

Variant names:

• chr6-35505751-C-G
• NM_003322.6:c.1102G>C
• TULP1 p.Gly368Arg

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS1 PM2 PM5 PP2 PP3_Strong PP5

The NM_003322.6(TULP1):​c.1102G>C​(p.Gly368Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G368W) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TULP1 NM_003322.6 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.90
• 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: Pathogenic. The variant received 14 ACMG points.

• PS1: Transcript NM_003322.6 (TULP1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-35505751-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 30262.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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 6-35505751-C-G is Pathogenic according to our data. Variant chr6-35505751-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3248791.Status of the report is no_assertion_criteria_provided, 0 stars.

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.1102G>C	p.Gly368Arg	missense	Exon 11 of 15	NP_003313.3
	TULP1	NM_001289395.2		c.943G>C	p.Gly315Arg	missense	Exon 10 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.1102G>C	p.Gly368Arg	missense	Exon 11 of 15	ENSP00000229771.6	O00294-1
	TULP1	ENST00000322263.8	TSL:1	c.943G>C	p.Gly315Arg	missense	Exon 10 of 14	ENSP00000319414.4	O00294-2
	TULP1	ENST00000614066.4	TSL:5	c.1096G>C	p.Gly366Arg	missense	Exon 10 of 14	ENSP00000477534.1	A0A087WT25

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.68	D
BayesDel_noAF	Pathogenic	0.74
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		7.9
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-7.9	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R		0.99
gMVP		0.94
Mutation Taster		=6/94	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr6-35473528;