16-89746685-G-C

Variant names:

• chr16-89746685-G-C
• rs138417003
• NM_000135.4:c.3412C>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000135.4(FANCA):​c.3412C>G​(p.Leu1138Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00082 in 1,614,004 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1138F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00070 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00083 (13 hom.)
• Consequence: FANCA NM_000135.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14 O:1
• Conservation: PhyloP100: 3.07
• Publications: 10 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 -18 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 22 uncertain in NM_000135.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.011628985).
• BP6: Variant 16-89746685-G-C is Benign according to our data. Variant chr16-89746685-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000696 (106/152356) while in subpopulation SAS AF = 0.0106 (51/4824). AF 95% confidence interval is 0.00826. There are 2 homozygotes in GnomAd4. There are 77 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 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.3412C>G	p.Leu1138Val	missense	Exon 35 of 43	NP_000126.2	O15360-1
	FANCA	NM_001286167.3		c.3412C>G	p.Leu1138Val	missense	Exon 35 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.3412C>G	p.Leu1138Val	missense	Exon 35 of 43	ENSP00000373952.3	O15360-1
	FANCA	ENST00000564475.6	TSL:2	c.3412C>G	p.Leu1138Val	missense	Exon 35 of 42	ENSP00000454977.2	H3BNS0
	FANCA	ENST00000568369.6	TSL:2	c.3412C>G	p.Leu1138Val	missense	Exon 35 of 43	ENSP00000456829.1	O15360-3

Frequencies

GnomAD3 genomes AF: 0.000696 AC: 106 AN: 152238 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00150 AC: 377 AN: 251228 AF XY: 0.00189

Gnomad AFR exome AF: 0.000739

Gnomad AMR exome AF: 0.000839

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000361

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.000833 AC: 1217 AN: 1461648 Hom.: 13 Cov.: 31 AF XY: 0.00115 AC XY: 836 AN XY: 727144

African (AFR) AF: 0.000568 AC: 19 AN: 33480

American (AMR) AF: 0.000738 AC: 33 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.0105 AC: 908 AN: 86234

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53352

Middle Eastern (MID) AF: 0.00780 AC: 45 AN: 5768

European-Non Finnish (NFE) AF: 0.000135 AC: 150 AN: 1111876

Other (OTH) AF: 0.000994 AC: 60 AN: 60388

GnomAD4 genome AF: 0.000696 AC: 106 AN: 152356 Hom.: 2 Cov.: 32 AF XY: 0.00103 AC XY: 77 AN XY: 74496

African (AFR) AF: 0.000745 AC: 31 AN: 41592

American (AMR) AF: 0.000261 AC: 4 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.0106 AC: 51 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68034

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000272 Hom.: 0

Bravo AF: 0.000446

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00152 AC: 185

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Fanconi anemia complementation group A (5)
-	-	5	not specified (6)
-	-	2	Fanconi anemia (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.010
CADD	Benign	19
DANN	Benign	0.91
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	0.45	D
MutationAssessor	Benign	1.8	L
PhyloP100		3.1
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.43
Sift	Benign	0.18	T
Sift4G	Benign	0.21	T
Polyphen		0.91	P
Vest4		0.26
MVP		0.89
ClinPred		0.043	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.34
Mutation Taster		=97/3	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: rs138417003; hg19: chr16-89813093; COSMIC: COSV59796302;