9-95149989-T-C

Variant names:

• chr9-95149989-T-C
• rs202038890
• NM_000136.3:c.620A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000136.3(FANCC):​c.620A>G​(p.His207Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,516 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H207L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: FANCC NM_000136.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.03
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCC	NM_000136.3	MANE Select	c.620A>G	p.His207Arg	missense	Exon 7 of 15	NP_000127.2
	FANCC	NM_001243743.2		c.620A>G	p.His207Arg	missense	Exon 7 of 15	NP_001230672.1
	FANCC	NM_001243744.2		c.620A>G	p.His207Arg	missense	Exon 7 of 14	NP_001230673.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCC	ENST00000289081.8	TSL:1 MANE Select	c.620A>G	p.His207Arg	missense	Exon 7 of 15	ENSP00000289081.3
	FANCC	ENST00000375305.6	TSL:1	c.620A>G	p.His207Arg	missense	Exon 7 of 15	ENSP00000364454.1
	FANCC	ENST00000490972.7	TSL:1	c.620A>G	p.His207Arg	missense	Exon 7 of 14	ENSP00000479931.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250616 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461516 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726990

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000448 AC: 2 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86116

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111876

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Dec 10, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.H207R variant (also known as c.620A>G), located in coding exon 6 of the FANCC gene, results from an A to G substitution at nucleotide position 620. The histidine at codon 207 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	D
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.0
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Benign	0.17
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.014	D
Polyphen		0.11	B
Vest4		0.43
MutPred		0.82		Loss of catalytic residue at I205 (P = 0.0951)
MVP		0.71
MPC		0.28
ClinPred		0.79	D
GERP RS		3.6
Varity_R		0.32
gMVP		0.41
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs202038890; hg19: chr9-97912271;