NM_000135.4:c.2574C>G

Variant names:

• chr16-89767168-G-C
• rs17233141
• NM_000135.4:c.2574C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000135.4(FANCA):​c.2574C>G​(p.Ser858Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00896 in 1,613,284 control chromosomes in the GnomAD database, including 135 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. S858T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0064 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0092 (128 hom.)
• Consequence: FANCA NM_000135.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:2 B:17 O:1
• Conservation: PhyloP100: 1.79
• Publications: 38 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008692145).
• BP6: Variant 16-89767168-G-C is Benign according to our data. Variant chr16-89767168-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134256.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 = 0.0064 (975/152350) while in subpopulation SAS AF = 0.0255 (123/4826). AF 95% confidence interval is 0.0218. There are 7 homozygotes in GnomAd4. There are 481 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.2574C>G	p.Ser858Arg	missense	Exon 27 of 43	NP_000126.2	O15360-1
	FANCA	NM_001286167.3		c.2574C>G	p.Ser858Arg	missense	Exon 27 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.2574C>G	p.Ser858Arg	missense	Exon 27 of 43	ENSP00000373952.3	O15360-1
	FANCA	ENST00000567205.2	TSL:1	n.*195C>G		non_coding_transcript_exon	Exon 27 of 27	ENSP00000457027.2	H3BT53
	FANCA	ENST00000567205.2	TSL:1	n.*195C>G		3_prime_UTR	Exon 27 of 27	ENSP00000457027.2	H3BT53

Frequencies

GnomAD3 genomes AF: 0.00642 AC: 978 AN: 152232 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.00176

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00674

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0261

Gnomad FIN AF: 0.00810

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00794

Gnomad OTH AF: 0.00908

GnomAD2 exomes AF: 0.0100 AC: 2527 AN: 251444 AF XY: 0.0117

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00402

Gnomad ASJ exome AF: 0.0112

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0101

Gnomad NFE exome AF: 0.00871

Gnomad OTH exome AF: 0.0111

GnomAD4 exome AF: 0.00922 AC: 13475 AN: 1460934 Hom.: 128 Cov.: 30 AF XY: 0.00995 AC XY: 7234 AN XY: 726846

African (AFR) AF: 0.00122 AC: 41 AN: 33470

American (AMR) AF: 0.00429 AC: 192 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0111 AC: 291 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0324 AC: 2796 AN: 86232

European-Finnish (FIN) AF: 0.00929 AC: 496 AN: 53382

Middle Eastern (MID) AF: 0.0250 AC: 144 AN: 5768

European-Non Finnish (NFE) AF: 0.00802 AC: 8913 AN: 1111190

Other (OTH) AF: 0.00998 AC: 602 AN: 60350

GnomAD4 genome AF: 0.00640 AC: 975 AN: 152350 Hom.: 7 Cov.: 33 AF XY: 0.00646 AC XY: 481 AN XY: 74494

African (AFR) AF: 0.00176 AC: 73 AN: 41582

American (AMR) AF: 0.00673 AC: 103 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00692 AC: 24 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5194

South Asian (SAS) AF: 0.0255 AC: 123 AN: 4826

European-Finnish (FIN) AF: 0.00810 AC: 86 AN: 10612

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00794 AC: 540 AN: 68040

Other (OTH) AF: 0.00899 AC: 19 AN: 2114

Alfa AF: 0.00831 Hom.: 2

Bravo AF: 0.00565

TwinsUK AF: 0.00998 AC: 37

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00721 AC: 62

ExAC AF: 0.0103 AC: 1250

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.00927

EpiControl AF: 0.00812

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	4	Fanconi anemia complementation group A (6)
-	-	6	not provided (6)
-	-	4	not specified (5)
-	-	2	Fanconi anemia (2)
-	-	1	FANCA-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	9.9
DANN	Benign	0.93
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.093	N
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.0087	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.8
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.13
Sift	Benign	0.063	T
Sift4G	Benign	0.072	T
Polyphen		0.26	B
Vest4		0.34
MutPred		0.25		Gain of MoRF binding (P = 0.054)
ClinPred		0.0082	T
GERP RS		1.6
Varity_R		0.069
gMVP		0.17
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs17233141; hg19: chr16-89833576; COSMIC: COSV59796377;