16-89816615-T-G

Variant names:

• chr16-89816615-T-G
• rs772751654
• NM_000135.4:c.1A>C

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.1A>C​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000328 in 1,524,084 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: 𝑓 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: FANCA NM_000135.4 initiator_codon
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 0.666
• 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 as 553965
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-89816615-T-G is Pathogenic according to our data. Variant chr16-89816615-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 553521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCA	NM_000135.4	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 43	ENST00000389301.8	NP_000126.2
FANCA	NM_001286167.3	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 43		NP_001273096.1
FANCA	NM_001018112.3	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 11		NP_001018122.1
FANCA	NM_001351830.2	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 10		NP_001338759.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCA	ENST00000389301.8	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 43	1	NM_000135.4	ENSP00000373952.3

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152024 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000250 AC: 3 AN: 120082 AF XY: 0.0000300

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000858

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000292 AC: 4 AN: 1372060 Hom.: 0 Cov.: 31 AF XY: 0.00000295 AC XY: 2 AN XY: 677814

African (AFR) AF: 0.00 AC: 0 AN: 29092

American (AMR) AF: 0.0000565 AC: 2 AN: 35376

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24704

East Asian (EAS) AF: 0.0000293 AC: 1 AN: 34160

South Asian (SAS) AF: 0.0000128 AC: 1 AN: 77986

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4276

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1075636

Other (OTH) AF: 0.00 AC: 0 AN: 57228

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152024 Hom.: 0 Cov.: 34 AF XY: 0.0000135 AC XY: 1 AN XY: 74278

African (AFR) AF: 0.0000241 AC: 1 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67964

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000107 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group A Pathogenic:3

Apr 05, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 16, 2021

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000135.2(FANCA):c.1A>C(M1?) is an initiation codon variant classified as pathogenic in the context of Fanconi anemia complementation group A. M1? has been observed in cases with relevant disease (PMID: 29098742). Functional assessments of this variant are not available in the literature. M1? has been observed in population frequency databases (gnomAD: AMR 0.01%). In summary, NM_000135.2(FANCA):c.1A>C(M1?) is an initiation codon variant in a gene where loss of function is a known mechanism of disease and is predicted to disrupt protein function. Please note: this variant was assessed in the context of healthy population screening. -

Feb 28, 2020

Leiden Open Variation Database

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

Curator: Arleen D. Auerbach. Submitter to LOVD: Sue Richards. -

not provided Pathogenic:2

Mar 28, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The FANCA c.1A>C variant disrupts the translation initiation codon of the FANCA mRNA and is predicted to interfere with FANCA protein synthesis. This variant has been reported in the published literature in in individuals and families with Fanconi anemia (PMIDs: 29098742 (2018) and 35417938 (2023)), as well as colon adenocarcinoma (PMIDs: 29625052 (2018) and 36451132 (2022)). The frequency of this variant in the general population, 0.000025 (3/120082 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, this variant is classified as likely pathogenic. -

Dec 21, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in patients with Fanconi anemia who also possessed another FANCA variant (PMID: 29098742); Initiation codon variant in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 10090479, 16084127, 24584348, 23898106, 29625052, 15643609, 29098742, 30031030, 30792206, 36451132) -

Fanconi anemia Pathogenic:1

Sep 26, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the FANCA mRNA. The next in-frame methionine is located at codon 116. This variant is present in population databases (rs772751654, gnomAD 0.009%). Disruption of the initiator codon has been observed in individuals with Fanconi anemia (PMID: 10090479, 15643609, 16084127, 23898106, 24584348). ClinVar contains an entry for this variant (Variation ID: 553521). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.27
CADD	Benign	17
DANN	Benign	0.72
DEOGEN2	Benign	0.072	T;.;.;T;T;.
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.64
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Benign	-0.47	T
PhyloP100		0.67
PROVEAN	Benign	-0.80	N;N;N;N;N;N
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		0.064	B;.;.;.;B;B
Vest4		0.77
MutPred		1.0		Loss of phosphorylation at S2 (P = 0.1776);Loss of phosphorylation at S2 (P = 0.1776);Loss of phosphorylation at S2 (P = 0.1776);Loss of phosphorylation at S2 (P = 0.1776);Loss of phosphorylation at S2 (P = 0.1776);Loss of phosphorylation at S2 (P = 0.1776);
MVP		0.86
ClinPred		0.96	D
GERP RS		3.1
PromoterAI		-0.14	Neutral
Varity_R		0.94
gMVP		0.15
Mutation Taster		=2/198	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: rs772751654; hg19: chr16-89883023;