16-89816614-A-T

Variant names:

• chr16-89816614-A-T
• rs769479800
• NM_000135.4:c.2T>A

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_000135.4(FANCA):​c.2T>A​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000729 in 1,372,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: FANCA NM_000135.4 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.06
• Publications: 15 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 20 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 84 pathogenic variants. Next in-frame start position is after 116 codons. Genomic position: 89811009. Lost 0.079 part of the original CDS.
• PS1: Another start lost variant in NM_000135.4 (FANCA) was described as [Likely_pathogenic] in ClinVar
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-89816614-A-T is Pathogenic according to our data. Variant chr16-89816614-A-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 556239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.2T>A	p.Met1?	start_lost	Exon 1 of 43	NP_000126.2
	FANCA	NM_001286167.3		c.2T>A	p.Met1?	start_lost	Exon 1 of 43	NP_001273096.1
	FANCA	NM_001018112.3		c.2T>A	p.Met1?	start_lost	Exon 1 of 11	NP_001018122.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCA	ENST00000389301.8	TSL:1 MANE Select	c.2T>A	p.Met1?	start_lost	Exon 1 of 43	ENSP00000373952.3
	FANCA	ENST00000563673.5	TSL:1	c.2T>A	p.Met1?	start_lost	Exon 1 of 10	ENSP00000456443.1
	FANCA	ENST00000534992.5	TSL:1	c.2T>A	p.Met1?	start_lost	Exon 1 of 11	ENSP00000443675.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000829 AC: 1 AN: 120628 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000211

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.29e-7 AC: 1 AN: 1372296 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 677952

African (AFR) AF: 0.00 AC: 0 AN: 29116

American (AMR) AF: 0.00 AC: 0 AN: 35410

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24696

East Asian (EAS) AF: 0.00 AC: 0 AN: 34200

South Asian (SAS) AF: 0.00 AC: 0 AN: 77990

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4282

European-Non Finnish (NFE) AF: 9.30e-7 AC: 1 AN: 1075762

Other (OTH) AF: 0.00 AC: 0 AN: 57230

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000435 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group A Pathogenic:3

Mar 05, 2025

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000135.2(FANCA):c.2T>A(M1?) is an initiation codon variant classified as likely pathogenic in the context of Fanconi anemia complementation group A. c.2T>A has been observed in a case with relevant disease (PMID: 31130284). Relevant functional assessments of this variant are not available in the literature. c.2T>A has been observed in referenced population frequency databases. In summary, NM_000135.2(FANCA):c.2T>A(M1?) is an initiation codon variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

Jan 22, 2018

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Jun 26, 2023

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Fanconi anemia Pathogenic:1

Feb 13, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: FANCA c.2T>A (p.Met1Lys) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The next downstream Met is p.Met116. A different start-lost variant has been classified as Pathogenic by Labcorp (p.Met1Thr (c.2T>C)). Two of two in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.3e-06 in 120628 control chromosomes. c.2T>A has been reported in the homozygous and compound heterozygous state in the literature in multiple individuals affected with Fanconi Anemia (example, DeRocco_2014, Joshi_2023, Monies_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24584348, 36894310, 31130284). ClinVar contains an entry for this variant (Variation ID: 556239). Based on the evidence outlined above, the variant was classified as pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.091	T
Eigen	Benign	0.037
Eigen_PC	Benign	-0.089
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.35	D
PhyloP100		1.1
PROVEAN	Benign	-0.95	N
REVEL	Uncertain	0.44
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.85
MutPred		0.99		Gain of ubiquitination at M1 (P = 0.0117)
MVP		0.91
ClinPred		0.99	D
GERP RS		4.3
PromoterAI		-0.37	Neutral
Varity_R		0.96
gMVP		0.34
Mutation Taster		=1/199	disease causing (ClinVar)

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: rs769479800; hg19: chr16-89883022;