rs1800368

Variant names:

• chr9-95107205-T-C
• rs1800368
• NM_000136.3:c.1394A>G

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.1394A>G​(p.Gln465Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000643 in 1,614,178 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q465H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00037 (3 hom.)
• Consequence: FANCC NM_000136.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:13 O:1
• Conservation: PhyloP100: -1.73
• Publications: 12 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]

LOC107987102 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.003341049).
• BP6: Variant 9-95107205-T-C is Benign according to our data. Variant chr9-95107205-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134297.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 = 0.00326 (497/152316) while in subpopulation AFR AF = 0.0111 (461/41570). AF 95% confidence interval is 0.0103. There are 0 homozygotes in GnomAd4. There are 228 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 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.1394A>G	p.Gln465Arg	missense	Exon 14 of 15	NP_000127.2	Q00597
	FANCC	NM_001243743.2		c.1394A>G	p.Gln465Arg	missense	Exon 14 of 15	NP_001230672.1	A0A024R9N2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCC	ENST00000289081.8	TSL:1 MANE Select	c.1394A>G	p.Gln465Arg	missense	Exon 14 of 15	ENSP00000289081.3	Q00597
	FANCC	ENST00000375305.6	TSL:1	c.1394A>G	p.Gln465Arg	missense	Exon 14 of 15	ENSP00000364454.1	Q00597
	FANCC	ENST00000863590.1		c.1394A>G	p.Gln465Arg	missense	Exon 16 of 17	ENSP00000533649.1

Frequencies

GnomAD3 genomes AF: 0.00327 AC: 498 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.000828 AC: 208 AN: 251264 AF XY: 0.000552

Gnomad AFR exome AF: 0.0103

Gnomad AMR exome AF: 0.000752

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000370 AC: 541 AN: 1461862 Hom.: 3 Cov.: 32 AF XY: 0.000303 AC XY: 220 AN XY: 727224

African (AFR) AF: 0.0109 AC: 366 AN: 33478

American (AMR) AF: 0.000715 AC: 32 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86246

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53418

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5762

European-Non Finnish (NFE) AF: 0.0000495 AC: 55 AN: 1112004

Other (OTH) AF: 0.00116 AC: 70 AN: 60394

GnomAD4 genome AF: 0.00326 AC: 497 AN: 152316 Hom.: 0 Cov.: 33 AF XY: 0.00306 AC XY: 228 AN XY: 74478

African (AFR) AF: 0.0111 AC: 461 AN: 41570

American (AMR) AF: 0.00118 AC: 18 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68036

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00124 Hom.: 2

Bravo AF: 0.00339

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00953 AC: 42

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000980 AC: 119

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	3	Fanconi anemia complementation group C (3)
-	-	3	not specified (4)
-	-	1	Fanconi anemia (1)
-	-	1	Fanconi anemia complementation group A (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.016
DANN	Benign	0.25
DEOGEN2	Benign	0.052	T
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.17	T
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.4	N
PhyloP100		-1.7
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.76	N
REVEL	Benign	0.026
Sift	Benign	0.90	T
Sift4G	Benign	0.70	T
Polyphen		0.0	B
Vest4		0.022
MVP		0.35
MPC		0.055
ClinPred		0.00080	T
GERP RS		-9.1
Varity_R		0.017
gMVP		0.034
Mutation Taster		=95/5	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: rs1800368; hg19: chr9-97869487;