chr15-66349394-G-C

Variant names:

• chr15-66349394-G-C
• rs2063690
• NM_017858.3:c.332C>G

Variant summary

Our verdict is Benign. The variant received -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.

• 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
• Publications: 23 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
TIPIN	NM_017858.3	c.332C>G	p.Ala111Gly	missense_variant	Exon 5 of 8	ENST00000261881.9	NP_060328.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIPIN	ENST00000261881.9	c.332C>G	p.Ala111Gly	missense_variant	Exon 5 of 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

GnomAD2 exomes AF: 0.115 AC: 28991 AN: 251154 AF XY: 0.111

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 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

African (AFR) AF: 0.0717 AC: 2401 AN: 33470

American (AMR) AF: 0.158 AC: 7078 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 3419 AN: 26122

East Asian (EAS) AF: 0.368 AC: 14598 AN: 39680

South Asian (SAS) AF: 0.0967 AC: 8335 AN: 86160

European-Finnish (FIN) AF: 0.0829 AC: 4424 AN: 53364

Middle Eastern (MID) AF: 0.0995 AC: 574 AN: 5768

European-Non Finnish (NFE) AF: 0.0845 AC: 93888 AN: 1111670

Other (OTH) AF: 0.107 AC: 6437 AN: 60362

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

African (AFR) AF: 0.0752 AC: 3124 AN: 41522

American (AMR) AF: 0.131 AC: 1999 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 457 AN: 3468

East Asian (EAS) AF: 0.338 AC: 1748 AN: 5166

South Asian (SAS) AF: 0.110 AC: 530 AN: 4822

European-Finnish (FIN) AF: 0.0819 AC: 867 AN: 10590

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.0836 AC: 5684 AN: 67984

Other (OTH) AF: 0.110 AC: 232 AN: 2110

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;.;.;.
PhyloP100		9.7
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
Mutation Taster		=74/26	polymorphism (auto)

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

Other links and lift over

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