rs72936240

Variant names:

• chr2-111856852-G-A
• rs72936240
• NM_022662.4:c.1393C>T
• ANAPC1 p.Gln465*

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 8P and 8B. PVS1 BP6_Very_Strong

The NM_022662.4(ANAPC1):​c.1393C>T​(p.Gln465*) variant causes a stop gained change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.082 (0 hom., cov: 33)
  • Exomes 𝑓: 0.28 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ANAPC1 NM_022662.4 stop_gained
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.60
• Publications: 19 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, G2P

ACMG classification

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

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BP6: Variant 2-111856852-G-A is Benign according to our data. Variant chr2-111856852-G-A is described in ClinVar as Benign. ClinVar VariationId is 402367.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1393C>T	p.Gln465*	stop_gained	Exon 12 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.1393C>T	p.Gln465*	stop_gained	Exon 12 of 48	ENSP00000339109.3	Q9H1A4
	ANAPC1	ENST00000917121.1		c.1393C>T	p.Gln465*	stop_gained	Exon 12 of 48	ENSP00000587180.1
	ANAPC1	ENST00000917126.1		c.1393C>T	p.Gln465*	stop_gained	Exon 12 of 48	ENSP00000587185.1

Frequencies

GnomAD3 genomes AF: 0.0816 AC: 6366 AN: 78002 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0600

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.0924

Gnomad ASJ AF: 0.0697

Gnomad EAS AF: 0.0943

Gnomad SAS AF: 0.116

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.0811

Gnomad OTH AF: 0.132

GnomAD2 exomes AF: 0.324 AC: 57495 AN: 177304 AF XY: 0.332

Gnomad AFR exome AF: 0.251

Gnomad AMR exome AF: 0.269

Gnomad ASJ exome AF: 0.349

Gnomad EAS exome AF: 0.191

Gnomad FIN exome AF: 0.426

Gnomad NFE exome AF: 0.354

Gnomad OTH exome AF: 0.287

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.282 AC: 272953 AN: 967794 Hom.: 0 Cov.: 53 AF XY: 0.277 AC XY: 134170 AN XY: 484398

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

African (AFR) AF: 0.211 AC: 4663 AN: 22146

American (AMR) AF: 0.210 AC: 6192 AN: 29538

Ashkenazi Jewish (ASJ) AF: 0.191 AC: 3079 AN: 16118

East Asian (EAS) AF: 0.0898 AC: 2358 AN: 26270

South Asian (SAS) AF: 0.180 AC: 10577 AN: 58734

European-Finnish (FIN) AF: 0.190 AC: 6447 AN: 33978

Middle Eastern (MID) AF: 0.219 AC: 615 AN: 2804

European-Non Finnish (NFE) AF: 0.311 AC: 229842 AN: 739592

Other (OTH) AF: 0.238 AC: 9180 AN: 38614

⚠️ 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: AS_VQSR AF: 0.0816 AC: 6368 AN: 78084 Hom.: 0 Cov.: 33 AF XY: 0.0849 AC XY: 3287 AN XY: 38726

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

African (AFR) AF: 0.0601 AC: 1354 AN: 22514

American (AMR) AF: 0.0922 AC: 723 AN: 7844

Ashkenazi Jewish (ASJ) AF: 0.0697 AC: 118 AN: 1694

East Asian (EAS) AF: 0.0944 AC: 267 AN: 2828

South Asian (SAS) AF: 0.115 AC: 274 AN: 2382

European-Finnish (FIN) AF: 0.130 AC: 680 AN: 5242

Middle Eastern (MID) AF: 0.135 AC: 17 AN: 126

European-Non Finnish (NFE) AF: 0.0811 AC: 2759 AN: 34020

Other (OTH) AF: 0.130 AC: 137 AN: 1056

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.213 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.94	D
PhyloP100		6.6
PromoterAI		-0.0024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.24		Position offset: 34

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: rs72936240;

hg19: chr2-112614429;

COSMIC: COSV61974026;

COSMIC: COSV61974026;