16-89792505-C-T

Variant names:

• chr16-89792505-C-T
• rs199967286
• NM_000135.4:c.1049G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM1 BP4_Strong BS1_Supporting BS2

The NM_000135.4(FANCA):​c.1049G>A​(p.Arg350Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000164 in 1,613,430 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R350W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (2 hom.)
• Consequence: FANCA NM_000135.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2 O:1
• Conservation: PhyloP100: 0.0850
• Publications: 6 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: Ambry Genetics, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), ClinGen, G2P, Myriad Women’s Health
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 22 uncertain in NM_000135.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.044961184).
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.00017 (248/1461158) while in subpopulation EAS AF = 0.00534 (212/39694). AF 95% confidence interval is 0.00475. There are 2 homozygotes in GnomAdExome4. There are 112 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCA	NM_000135.4	MANE Select	c.1049G>A	p.Arg350Gln	missense	Exon 12 of 43	NP_000126.2	O15360-1
	FANCA	NM_001286167.3		c.1049G>A	p.Arg350Gln	missense	Exon 12 of 43	NP_001273096.1	O15360-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCA	ENST00000389301.8	TSL:1 MANE Select	c.1049G>A	p.Arg350Gln	missense	Exon 12 of 43	ENSP00000373952.3	O15360-1
	FANCA	ENST00000567205.2	TSL:1	n.1049G>A		non_coding_transcript_exon	Exon 12 of 27	ENSP00000457027.2	H3BT53
	FANCA	ENST00000564475.6	TSL:2	c.1049G>A	p.Arg350Gln	missense	Exon 12 of 42	ENSP00000454977.2	H3BNS0

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000133 AC: 33 AN: 249016 AF XY: 0.000126

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00158

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000269

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000170 AC: 248 AN: 1461158 Hom.: 2 Cov.: 32 AF XY: 0.000154 AC XY: 112 AN XY: 726874

African (AFR) AF: 0.0000299 AC: 1 AN: 33460

American (AMR) AF: 0.0000224 AC: 1 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00534 AC: 212 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5222

European-Non Finnish (NFE) AF: 0.0000288 AC: 32 AN: 1111988

Other (OTH) AF: 0.0000166 AC: 1 AN: 60336

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152272 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74468

African (AFR) AF: 0.0000241 AC: 1 AN: 41560

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00232 AC: 12 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000670 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.000123 AC: 15

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	Fanconi anemia (3)
-	2	-	Fanconi anemia complementation group A (2)
-	1	1	not provided (2)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.26	N
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.085
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.13
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.032	D
Polyphen		0.91	P
Vest4		0.48
MVP		0.81
ClinPred		0.056	T
GERP RS		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.088
gMVP		0.22
Mutation Taster		=98/2	polymorphism

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: rs199967286; hg19: chr16-89858913; COSMIC: COSV66880070;