2-111778702-C-T

Variant names:

• chr2-111778702-C-T
• rs745357859
• NM_022662.4:c.5358G>A
• ANAPC1 p.Met1786Ile

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_022662.4(ANAPC1):​c.5358G>A​(p.Met1786Ile) variant causes a missense change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 22)
  • Exomes 𝑓: 0.000012 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ANAPC1 NM_022662.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.34
• Publications: 0 publications found

Genes affected

ANAPC1 (HGNC:19988): (anaphase promoting complex subunit 1) This gene encodes a subunit of the anaphase-promoting complex. This complex is an E3 ubiquitin ligase that regulates progression through the metaphase to anaphase portion of the cell cycle by ubiquitinating proteins which targets them for degradation. [provided by RefSeq, Dec 2011]

ANAPC1 Gene-Disease associations (from GenCC):

• Rothmund-Thomson syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: ClinGen, Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022662.4. 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
	ANAPC1	NM_022662.4	MANE Select	c.5358G>A	p.Met1786Ile	missense	Exon 45 of 48	NP_073153.1	Q9H1A4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANAPC1	ENST00000341068.8	TSL:1 MANE Select	c.5358G>A	p.Met1786Ile	missense	Exon 45 of 48	ENSP00000339109.3	Q9H1A4
	ANAPC1	ENST00000427997.5	TSL:1	c.3960G>A	p.Met1320Ile	missense	Exon 34 of 37	ENSP00000396695.1	H0Y564
	ANAPC1	ENST00000917121.1		c.5358G>A	p.Met1786Ile	missense	Exon 45 of 48	ENSP00000587180.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 139520 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000244 AC: 6 AN: 245522 AF XY: 0.0000226

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000275

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000117 AC: 17 AN: 1458050 Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9 AN XY: 725428

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33430

American (AMR) AF: 0.00 AC: 0 AN: 44142

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26026

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39590

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85942

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53138

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1109830

Other (OTH) AF: 0.00 AC: 0 AN: 60212

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 139520 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 67072

African (AFR) AF: 0.00 AC: 0 AN: 38746

American (AMR) AF: 0.00 AC: 0 AN: 12862

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3346

East Asian (EAS) AF: 0.00 AC: 0 AN: 4802

South Asian (SAS) AF: 0.00 AC: 0 AN: 4066

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64282

Other (OTH) AF: 0.00 AC: 0 AN: 1864

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0057	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.0097	T
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.8	L
PhyloP100		7.3
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.23
Sift	Benign	0.25	T
Sift4G	Benign	0.39	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.60
Mutation Taster		=70/30	polymorphism

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

dbSNP: rs745357859; hg19: chr2-112536279;