rs1800362

Variant names:

• chr9-95172077-C-T
• rs1800362
• NM_000136.3:c.416G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-95172077-C-T
• chr9-95172077-C-A

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.416G>A​(p.Gly139Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00256 in 1,612,860 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts 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. G139R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.014 (41 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (37 hom.)
• Consequence: FANCC NM_000136.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:16 O:1
• Conservation: PhyloP100: 3.06
• 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]

FANCC Gene-Disease associations (from GenCC):

• Fanconi anemia complementation group C

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), ClinGen, G2P
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• colorectal cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• malignant pancreatic neoplasm

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• ovarian cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• prostate cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.009651393).
• BP6: Variant 9-95172077-C-T is Benign according to our data. Variant chr9-95172077-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134304.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 = 0.0136 (2064/152124) while in subpopulation AFR AF = 0.0464 (1922/41466). AF 95% confidence interval is 0.0446. There are 41 homozygotes in GnomAd4. There are 969 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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.416G>A	p.Gly139Glu	missense	Exon 5 of 15	NP_000127.2	Q00597
	FANCC	NM_001243743.2		c.416G>A	p.Gly139Glu	missense	Exon 5 of 15	NP_001230672.1	A0A024R9N2
	FANCC	NM_001243744.2		c.416G>A	p.Gly139Glu	missense	Exon 5 of 14	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.416G>A	p.Gly139Glu	missense	Exon 5 of 15	ENSP00000289081.3	Q00597
	FANCC	ENST00000375305.6	TSL:1	c.416G>A	p.Gly139Glu	missense	Exon 5 of 15	ENSP00000364454.1	Q00597
	FANCC	ENST00000490972.7	TSL:1	c.416G>A	p.Gly139Glu	missense	Exon 5 of 14	ENSP00000479931.1	A0A087WW44

Frequencies

GnomAD3 genomes AF: 0.0136 AC: 2061 AN: 152006 Hom.: 41 Cov.: 32

Gnomad AFR AF: 0.0464

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00629

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: 0.000265

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.00348 AC: 873 AN: 251150 AF XY: 0.00262

Gnomad AFR exome AF: 0.0468

Gnomad AMR exome AF: 0.00237

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.00141 AC: 2060 AN: 1460736 Hom.: 37 Cov.: 29 AF XY: 0.00124 AC XY: 902 AN XY: 726760

African (AFR) AF: 0.0480 AC: 1604 AN: 33398

American (AMR) AF: 0.00291 AC: 130 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39610

South Asian (SAS) AF: 0.000267 AC: 23 AN: 86226

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53410

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5758

European-Non Finnish (NFE) AF: 0.0000900 AC: 100 AN: 1111160

Other (OTH) AF: 0.00315 AC: 190 AN: 60336

GnomAD4 genome AF: 0.0136 AC: 2064 AN: 152124 Hom.: 41 Cov.: 32 AF XY: 0.0130 AC XY: 969 AN XY: 74370

African (AFR) AF: 0.0464 AC: 1922 AN: 41466

American (AMR) AF: 0.00628 AC: 96 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

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

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

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

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68006

Other (OTH) AF: 0.0118 AC: 25 AN: 2112

Alfa AF: 0.00538 Hom.: 57

Bravo AF: 0.0153

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0449 AC: 198

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00422 AC: 513

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	-	4	not specified (5)
-	-	2	Fanconi anemia (2)
-	-	2	Fanconi anemia complementation group C (2)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	Fanconi anemia complementation group A (1)
-	-	1	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0097	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.1
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Benign	0.27
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.56
MVP		0.92
MPC		0.19
ClinPred		0.024	T
GERP RS		5.3
Varity_R		0.72
gMVP		0.72
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1800362; hg19: chr9-97934359; COSMIC: COSV99057233;