9-95099155-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000136.3(FANCC):c.*2552T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.026 in 215,522 control chromosomes in the GnomAD database, including 107 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.027 (84 hom., cov: 31)
  • Exomes 𝑓: 0.023 (23 hom.)
• Consequence: FANCC NM_000136.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.24

Genes affected

FANCC (HGNC:3584): (FA complementation group C) The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2). The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation group C. [provided by RefSeq, Jul 2008]

AOPEP (HGNC:1361): (aminopeptidase O (putative)) This gene encodes a member of the M1 zinc aminopeptidase family. The encoded protein is a zinc-dependent metallopeptidase that catalyzes the removal of an amino acid from the amino terminus of a protein or peptide. This protein may play a role in the generation of angiotensin IV. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Oct 2010]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BP6: Variant 9-95099155-A-G is Benign according to our data. Variant chr9-95099155-A-G is described in ClinVar as [Benign]. Clinvar id is 367569.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0272 (4138/152310) while in subpopulation AMR AF= 0.0433 (662/15306). AF 95% confidence interval is 0.0405. There are 84 homozygotes in gnomad4. There are 2057 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 84 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCC	NM_000136.3	c.*2552T>C		3_prime_UTR_variant	15/15	ENST00000289081.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCC	ENST00000289081.8	c.*2552T>C		3_prime_UTR_variant	15/15	1	NM_000136.3	P1
FANCC	ENST00000375305.6	c.*2552T>C		3_prime_UTR_variant	15/15	1		P1
AOPEP	ENST00000710812.1	n.410+18375A>G		intron_variant, non_coding_transcript_variant
FANCC	ENST00000696260.1			downstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.0272 AC: 4138 AN: 152192 Hom.: 84 Cov.: 31

Gnomad AFR AF: 0.00644

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0431

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0220

Gnomad FIN AF: 0.0544

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0357

Gnomad OTH AF: 0.0263

GnomAD4 exome AF: 0.0231 AC: 1463 AN: 63212 Hom.: 23 Cov.: 0 AF XY: 0.0233 AC XY: 682 AN XY: 29312

Gnomad4 AFR exome AF: 0.00495

Gnomad4 AMR exome AF: 0.0486

Gnomad4 ASJ exome AF: 0.00939

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0148

Gnomad4 FIN exome AF: 0.0370

Gnomad4 NFE exome AF: 0.0305

Gnomad4 OTH exome AF: 0.0231

GnomAD4 genome AF: 0.0272 AC: 4138 AN: 152310 Hom.: 84 Cov.: 31 AF XY: 0.0276 AC XY: 2057 AN XY: 74482

Gnomad4 AFR AF: 0.00642

Gnomad4 AMR AF: 0.0433

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0218

Gnomad4 FIN AF: 0.0544

Gnomad4 NFE AF: 0.0357

Gnomad4 OTH AF: 0.0260

Alfa AF: 0.0311 Hom.: 83

Bravo AF: 0.0248

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Fanconi anemia complementation group C Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
Cadd	Benign	0.087
Dann	Benign	0.28

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: rs9673; hg19: chr9-97861437;