15-66349394-G-C

Position:

• chr15-66349394-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_017858.3(TIPIN):​c.332C>G​(p.Ala111Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0966 in 1,613,398 control chromosomes in the GnomAD database, including 9,765 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.097 (911 hom., cov: 31)
  • Exomes 𝑓: 0.097 (8854 hom.)
• Consequence: TIPIN NM_017858.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.72

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003534168).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.325 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TIPIN	NM_017858.3	c.332C>G	p.Ala111Gly	missense_variant	5/8	ENST00000261881.9	NP_060328.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TIPIN	ENST00000261881.9	c.332C>G	p.Ala111Gly	missense_variant	5/8	1	NM_017858.3	ENSP00000261881.4

Frequencies

GnomAD3 genomes AF: 0.0968 AC: 14723 AN: 152022 Hom.: 911 Cov.: 31

Gnomad AFR AF: 0.0754

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.131

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.338

Gnomad SAS AF: 0.111

Gnomad FIN AF: 0.0819

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.0836

Gnomad OTH AF: 0.110

GnomAD3 exomes AF: 0.115 AC: 28991 AN: 251154 Hom.: 2364 AF XY: 0.111 AC XY: 15121 AN XY: 135748

Gnomad AFR exome AF: 0.0730

Gnomad AMR exome AF: 0.161

Gnomad ASJ exome AF: 0.129

Gnomad EAS exome AF: 0.338

Gnomad SAS exome AF: 0.0959

Gnomad FIN exome AF: 0.0812

Gnomad NFE exome AF: 0.0824

Gnomad OTH exome AF: 0.111

GnomAD4 exome AF: 0.0966 AC: 141154 AN: 1461258 Hom.: 8854 Cov.: 32 AF XY: 0.0962 AC XY: 69931 AN XY: 726924

Gnomad4 AFR exome AF: 0.0717

Gnomad4 AMR exome AF: 0.158

Gnomad4 ASJ exome AF: 0.131

Gnomad4 EAS exome AF: 0.368

Gnomad4 SAS exome AF: 0.0967

Gnomad4 FIN exome AF: 0.0829

Gnomad4 NFE exome AF: 0.0845

Gnomad4 OTH exome AF: 0.107

GnomAD4 genome AF: 0.0967 AC: 14718 AN: 152140 Hom.: 911 Cov.: 31 AF XY: 0.0980 AC XY: 7290 AN XY: 74378

Gnomad4 AFR AF: 0.0752

Gnomad4 AMR AF: 0.131

Gnomad4 ASJ AF: 0.132

Gnomad4 EAS AF: 0.338

Gnomad4 SAS AF: 0.110

Gnomad4 FIN AF: 0.0819

Gnomad4 NFE AF: 0.0836

Gnomad4 OTH AF: 0.110

Alfa AF: 0.0896 Hom.: 634

Bravo AF: 0.102

TwinsUK AF: 0.0847 AC: 314

ALSPAC AF: 0.0893 AC: 344

ESP6500AA AF: 0.0750 AC: 330

ESP6500EA AF: 0.0860 AC: 739

ExAC AF: 0.112 AC: 13570

Asia WGS AF: 0.205 AC: 709 AN: 3478

EpiCase AF: 0.0866

EpiControl AF: 0.0849

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.018	T;.;.;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D;D
MetaRNN	Benign	0.0035	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.0	M;.;.;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-2.2	N;N;N;D
REVEL	Benign	0.22
Sift	Benign	0.24	T;T;T;T
Sift4G	Benign	0.062	T;.;.;.
Polyphen		0.60	P;.;.;.
Vest4		0.27
MPC		0.28
ClinPred		0.032	T
GERP RS		5.5
Varity_R		0.33
gMVP		0.41

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: rs2063690; hg19: chr15-66641732; COSMIC: COSV56019642; COSMIC: COSV56019642;