chr6-35498344-T-G

Position:

• chr6-35498344-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003322.6(TULP1):​c.1612A>C​(p.Lys538Gln) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TULP1 NM_003322.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.01

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.876

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TULP1	NM_003322.6	c.1612A>C	p.Lys538Gln	missense_variant	15/15	ENST00000229771.11	NP_003313.3
TULP1	NM_001289395.2	c.1453A>C	p.Lys485Gln	missense_variant	14/14		NP_001276324.1
LOC124901309	XR_007059561.1	n.75+137T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TULP1	ENST00000229771.11	c.1612A>C	p.Lys538Gln	missense_variant	15/15	1	NM_003322.6	ENSP00000229771.6
TULP1	ENST00000322263.8	c.1453A>C	p.Lys485Gln	missense_variant	14/14	1		ENSP00000319414.4
TULP1	ENST00000614066.4	c.1606A>C	p.Lys536Gln	missense_variant	14/14	5		ENSP00000477534.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Retinitis pigmentosa 14 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The missense variant p.K538Q in TULP1 (NM_003322.6) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.K538Q variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a small physicochemical difference between lysine and glutamine, which is not likely to impact secondary protein structure as these residues share similar properties. The p.K538Q missense variant is predicted to be damaging by both SIFT and PolyPhen2. The lysine residue at codon 538 of TULP1 is conserved in all mammalian species. The nucleotide c.1612 in TULP1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	.;D;T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	3.7	.;H;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.6	D;D;.
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.88
MutPred		0.34		.;Loss of ubiquitination at K538 (P = 0.0087);.;
MVP		0.91
MPC		0.95
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.94
gMVP		0.85

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-35466121;