ENST00000490972.7:c.1387C>T

Variant names:

• chr9-95111288-G-A
• rs112446681
• ENST00000490972.7:c.1387C>T

Variant summary

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

The ENST00000490972.7(FANCC):​c.1387C>T​(p.Arg463Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000826 in 1,569,554 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/10 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00051 (6 hom.)
• Consequence: FANCC ENST00000490972.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: -0.505
• Publications: 3 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 (MetaRNN=0.0038080513).
• BP6: Variant 9-95111288-G-A is Benign according to our data. Variant chr9-95111288-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134308.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 = 0.00378 (576/152298) while in subpopulation AFR AF = 0.0134 (555/41564). AF 95% confidence interval is 0.0124. There are 3 homozygotes in GnomAd4. There are 279 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000490972.7. 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.1329+175C>T		intron	N/A	NP_000127.2
	FANCC	NM_001243744.2		c.1387C>T	p.Arg463Cys	missense	Exon 14 of 14	NP_001230673.1
	FANCC	NM_001243743.2		c.1329+175C>T		intron	N/A	NP_001230672.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCC	ENST00000490972.7	TSL:1	c.1387C>T	p.Arg463Cys	missense	Exon 14 of 14	ENSP00000479931.1
	FANCC	ENST00000289081.8	TSL:1 MANE Select	c.1329+175C>T		intron	N/A	ENSP00000289081.3
	FANCC	ENST00000375305.6	TSL:1	c.1329+175C>T		intron	N/A	ENSP00000364454.1

Frequencies

GnomAD3 genomes AF: 0.00378 AC: 575 AN: 152182 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0134

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000976 AC: 177 AN: 181306 AF XY: 0.000727

Gnomad AFR exome AF: 0.0131

Gnomad AMR exome AF: 0.000903

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000594

Gnomad NFE exome AF: 0.0000625

Gnomad OTH exome AF: 0.00121

GnomAD4 exome AF: 0.000509 AC: 721 AN: 1417256 Hom.: 6 Cov.: 37 AF XY: 0.000472 AC XY: 332 AN XY: 703136

African (AFR) AF: 0.0148 AC: 482 AN: 32530

American (AMR) AF: 0.000882 AC: 35 AN: 39670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25594

East Asian (EAS) AF: 0.00 AC: 0 AN: 37450

South Asian (SAS) AF: 0.0000965 AC: 8 AN: 82870

European-Finnish (FIN) AF: 0.000247 AC: 9 AN: 36452

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5732

European-Non Finnish (NFE) AF: 0.0000683 AC: 75 AN: 1097640

Other (OTH) AF: 0.00172 AC: 102 AN: 59318

GnomAD4 genome AF: 0.00378 AC: 576 AN: 152298 Hom.: 3 Cov.: 33 AF XY: 0.00375 AC XY: 279 AN XY: 74464

African (AFR) AF: 0.0134 AC: 555 AN: 41564

American (AMR) AF: 0.000719 AC: 11 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68030

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.00551 Hom.: 4

Bravo AF: 0.00417

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00100 AC: 118

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Fanconi anemia (1)
-	-	1	Fanconi anemia complementation group C (1)
-	-	1	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	0.87
DANN	Benign	0.48
DEOGEN2	Benign	0.019	T
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.0038	T
PhyloP100		-0.51
Sift4G	Benign	0.090	T
Vest4		0.086
MVP		0.80
GERP RS		-2.8
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs112446681; hg19: chr9-97873570;