rs4647506

Variant names:

• chr9-95135342-G-A
• rs4647506
• NM_000136.3:c.843+4C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000136.3(FANCC):​c.843+4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00254 in 1,613,328 control chromosomes in the GnomAD database, including 76 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (41 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (35 hom.)
• Consequence: FANCC NM_000136.3 splice_region, intron
• Scores: Splicing: ADA: 0.0001987
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -0.896
• Publications: 1 publications found

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 9-95135342-G-A is Benign according to our data. Variant chr9-95135342-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220920.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0133 (2025/152076) while in subpopulation AFR AF = 0.0456 (1889/41470). AF 95% confidence interval is 0.0438. There are 41 homozygotes in GnomAd4. There are 941 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 41 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000136.3. 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
	FANCC	NM_000136.3	MANE Select	c.843+4C>T		splice_region intron	N/A	NP_000127.2	Q00597
	FANCC	NM_001243743.2		c.843+4C>T		splice_region intron	N/A	NP_001230672.1	A0A024R9N2
	FANCC	NM_001243744.2		c.843+4C>T		splice_region intron	N/A	NP_001230673.1	A0A087WW44

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCC	ENST00000289081.8	TSL:1 MANE Select	c.843+4C>T		splice_region intron	N/A	ENSP00000289081.3	Q00597
	FANCC	ENST00000375305.6	TSL:1	c.843+4C>T		splice_region intron	N/A	ENSP00000364454.1	Q00597
	FANCC	ENST00000490972.7	TSL:1	c.843+4C>T		splice_region intron	N/A	ENSP00000479931.1	A0A087WW44

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 2022 AN: 151958 Hom.: 41 Cov.: 33

Gnomad AFR AF: 0.0456

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00583

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.00344 AC: 865 AN: 251404 AF XY: 0.00257

Gnomad AFR exome AF: 0.0461

Gnomad AMR exome AF: 0.00234

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00142 AC: 2071 AN: 1461252 Hom.: 35 Cov.: 31 AF XY: 0.00123 AC XY: 895 AN XY: 726922

African (AFR) AF: 0.0474 AC: 1588 AN: 33468

American (AMR) AF: 0.00288 AC: 129 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.000302 AC: 26 AN: 86230

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53296

Middle Eastern (MID) AF: 0.00226 AC: 13 AN: 5756

European-Non Finnish (NFE) AF: 0.000110 AC: 122 AN: 1111592

Other (OTH) AF: 0.00315 AC: 190 AN: 60372

GnomAD4 genome AF: 0.0133 AC: 2025 AN: 152076 Hom.: 41 Cov.: 33 AF XY: 0.0127 AC XY: 941 AN XY: 74316

African (AFR) AF: 0.0456 AC: 1889 AN: 41470

American (AMR) AF: 0.00583 AC: 89 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10546

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68010

Other (OTH) AF: 0.0118 AC: 25 AN: 2114

Alfa AF: 0.00690 Hom.: 11

Bravo AF: 0.0149

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	Fanconi anemia complementation group C (3)
-	-	2	Fanconi anemia (2)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	not specified (2)
-	-	1	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.42
DANN	Benign	0.79
PhyloP100		-0.90
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00020
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.010		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: rs4647506; hg19: chr9-97897624;