9-95117389-A-T

Variant names:

• chr9-95117389-A-T
• rs864622191
• NM_000136.3:c.998T>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000136.3(FANCC):​c.998T>A​(p.Leu333Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,908 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L333P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FANCC NM_000136.3 missense, splice_region
• Scores: Splicing: ADA: 0.003217
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.672
• Publications: 0 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.801

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.998T>A	p.Leu333Gln	missense splice_region	Exon 11 of 15	NP_000127.2
	FANCC	NM_001243743.2		c.998T>A	p.Leu333Gln	missense splice_region	Exon 11 of 15	NP_001230672.1
	FANCC	NM_001243744.2		c.998T>A	p.Leu333Gln	missense splice_region	Exon 11 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.998T>A	p.Leu333Gln	missense splice_region	Exon 11 of 15	ENSP00000289081.3
	FANCC	ENST00000375305.6	TSL:1	c.998T>A	p.Leu333Gln	missense splice_region	Exon 11 of 15	ENSP00000364454.1
	FANCC	ENST00000490972.7	TSL:1	c.998T>A	p.Leu333Gln	missense splice_region	Exon 11 of 14	ENSP00000479931.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460908 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726698

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86004

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53120

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111704

Other (OTH) AF: 0.0000166 AC: 1 AN: 60322

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.024
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.019	T
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.67
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.33
Sift	Benign	0.16	T
Sift4G	Benign	0.071	T
Polyphen		0.99	D
Vest4		0.46
MutPred		0.80		Gain of disorder (P = 0.0205)
MVP		0.79
MPC		0.33
ClinPred		0.62	D
GERP RS		2.1
Varity_R		0.15
gMVP		0.17
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0032
dbscSNV1_RF	Benign	0.11
SpliceAI score (max)		0.40		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.40		Position offset: -2
DS_AL_spliceai		0.32		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs864622191; hg19: chr9-97879671;