NM_000135.4:c.971T>C

Variant names:

• chr16-89795941-A-G
• rs1447363475
• NM_000135.4:c.971T>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_000135.4(FANCA):​c.971T>C​(p.Leu324Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L324R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FANCA NM_000135.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.84
• Publications: 0 publications found

Genes affected

FANCA (HGNC:3582): (FA complementation group A) 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 A. Alternative splicing results in multiple transcript variants encoding different isoforms. Mutations in this gene are the most common cause of Fanconi anemia. [provided by RefSeq, Jul 2008]

FANCA Gene-Disease associations (from GenCC):

• Fanconi anemia complementation group A

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-89795941-A-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 456147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964
• PP5: Variant 16-89795941-A-G is Pathogenic according to our data. Variant chr16-89795941-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1707718.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000135.4. 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
	FANCA	NM_000135.4	MANE Select	c.971T>C	p.Leu324Pro	missense	Exon 11 of 43	NP_000126.2
	FANCA	NM_001286167.3		c.971T>C	p.Leu324Pro	missense	Exon 11 of 43	NP_001273096.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCA	ENST00000389301.8	TSL:1 MANE Select	c.971T>C	p.Leu324Pro	missense	Exon 11 of 43	ENSP00000373952.3
	FANCA	ENST00000566409.1	TSL:1	n.*235T>C		non_coding_transcript_exon	Exon 2 of 2	ENSP00000457647.1
	FANCA	ENST00000567205.2	TSL:1	n.971T>C		non_coding_transcript_exon	Exon 11 of 27	ENSP00000457027.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Fanconi anemia complementation group A Pathogenic:1

Cytogenetique et Genetique Moleculaire, CHU Besancon

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Compound heterozygous variant of FANCA with a well known pathogenic variant in trans (NM_000135.4:c.3391A>G) suggested by parental segregation (SANGER sequencing). Compatible phenotype with FANCONI ANEMIA, COMPLEMENTATION GROUP A; FANCA.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.055	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		6.8
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.74		Gain of loop (P = 0.0097)
MVP		0.83
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.90
gMVP		0.88
Mutation Taster		=22/78	disease causing

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: rs1447363475; hg19: chr16-89862349;