15-66337049-A-G

Variant names:

• chr15-66337049-A-G
• NM_017858.3:c.815T>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_017858.3(TIPIN):​c.815T>C​(p.Leu272Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TIPIN NM_017858.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.147

Genes affected

TIPIN (HGNC:30750): (TIMELESS interacting protein) The protein encoded by this gene is part of the replisome complex, a group of proteins that support DNA replication. It binds TIM, which is involved in circadian rhythm regulation, and aids in protecting cells against DNA damage and stress. Two pseudogenes and two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2014]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.047694385).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIPIN	NM_017858.3	c.815T>C	p.Leu272Ser	missense_variant	Exon 8 of 8	ENST00000261881.9	NP_060328.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIPIN	ENST00000261881.9	c.815T>C	p.Leu272Ser	missense_variant	Exon 8 of 8	1	NM_017858.3	ENSP00000261881.4
TIPIN	ENST00000562124.5	c.815T>C	p.Leu272Ser	missense_variant	Exon 8 of 8	5		ENSP00000457406.1
TIPIN	ENST00000566524.5	n.*514T>C		non_coding_transcript_exon_variant	Exon 7 of 7	2		ENSP00000455656.1
TIPIN	ENST00000566524.5	n.*514T>C		3_prime_UTR_variant	Exon 7 of 7	2		ENSP00000455656.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 04, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.815T>C (p.L272S) alteration is located in exon 8 (coding exon 7) of the TIPIN gene. This alteration results from a T to C substitution at nucleotide position 815, causing the leucine (L) at amino acid position 272 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	9.0
DANN	Benign	0.72
DEOGEN2	Benign	0.0064	T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.24	T;T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.048	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.14	N;N
REVEL	Benign	0.046
Sift	Benign	0.19	T;T
Sift4G	Benign	0.69	T;.
Polyphen		0.089	B;.
Vest4		0.082
MutPred		0.13		Loss of stability (P = 0.0297);Loss of stability (P = 0.0297);
MVP		0.23
MPC		0.15
ClinPred		0.094	T
GERP RS		1.0
Varity_R		0.044
gMVP		0.061

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: chr15-66629387;