NM_000136.3:c.346-18950T>A

Variant names:

• chr9-95191097-A-T
• rs242448
• NM_000136.3:c.346-18950T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000136.3(FANCC):​c.346-18950T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.938 in 152,146 control chromosomes in the GnomAD database, including 66,926 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.94 (66926 hom., cov: 30)
• Consequence: FANCC NM_000136.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.310
• 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]

FANCC Gene-Disease associations (from GenCC):

• Fanconi anemia complementation group C

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Myriad Women’s Health
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.935 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCC	NM_000136.3	c.346-18950T>A		intron_variant	Intron 4 of 14	ENST00000289081.8	NP_000127.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCC	ENST00000289081.8	c.346-18950T>A		intron_variant	Intron 4 of 14	1	NM_000136.3	ENSP00000289081.3

Frequencies

GnomAD3 genomes AF: 0.938 AC: 142591 AN: 152030 Hom.: 66877 Cov.: 30

Gnomad AFR AF: 0.943

Gnomad AMI AF: 0.973

Gnomad AMR AF: 0.918

Gnomad ASJ AF: 0.979

Gnomad EAS AF: 0.953

Gnomad SAS AF: 0.936

Gnomad FIN AF: 0.921

Gnomad MID AF: 0.981

Gnomad NFE AF: 0.938

Gnomad OTH AF: 0.948

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.938 AC: 142698 AN: 152146 Hom.: 66926 Cov.: 30 AF XY: 0.937 AC XY: 69700 AN XY: 74386

African (AFR) AF: 0.943 AC: 39119 AN: 41500

American (AMR) AF: 0.918 AC: 14037 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.979 AC: 3399 AN: 3472

East Asian (EAS) AF: 0.952 AC: 4914 AN: 5160

South Asian (SAS) AF: 0.936 AC: 4507 AN: 4814

European-Finnish (FIN) AF: 0.921 AC: 9752 AN: 10588

Middle Eastern (MID) AF: 0.979 AC: 286 AN: 292

European-Non Finnish (NFE) AF: 0.938 AC: 63799 AN: 68016

Other (OTH) AF: 0.949 AC: 1998 AN: 2106

Alfa AF: 0.941 Hom.: 7842

Bravo AF: 0.937

Asia WGS AF: 0.943 AC: 3280 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.59
DANN	Benign	0.43
PhyloP100		-0.31
Mutation Taster		=100/0	polymorphism (auto)

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: rs242448; hg19: chr9-97953379;