16-89739526-C-T

Variant names:

• chr16-89739526-C-T
• rs374649848
• NM_000135.4:c.3962G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1 BP4_Strong BP6

The NM_000135.4(FANCA):​c.3962G>A​(p.Arg1321His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000258 in 1,551,202 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. R1321C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: FANCA NM_000135.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: -0.796
• Publications: 4 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]

ZNF276 (HGNC:23330): (zinc finger protein 276) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Located in kinetochore. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 30 uncertain in NM_000135.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.05760309).
• BP6: Variant 16-89739526-C-T is Benign according to our data. Variant chr16-89739526-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 456125.

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.3962G>A	p.Arg1321His	missense	Exon 40 of 43	NP_000126.2	O15360-1
	ZNF276	NM_001113525.2	MANE Select	c.*1280C>T		3_prime_UTR	Exon 11 of 11	NP_001106997.1	Q8N554-1
	FANCA	NM_001286167.3		c.3962G>A	p.Arg1321His	missense	Exon 40 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.3962G>A	p.Arg1321His	missense	Exon 40 of 43	ENSP00000373952.3	O15360-1
	ZNF276	ENST00000443381.7	TSL:1 MANE Select	c.*1280C>T		3_prime_UTR	Exon 11 of 11	ENSP00000415836.2	Q8N554-1
	ZNF276	ENST00000289816.9	TSL:1	c.*1280C>T		3_prime_UTR	Exon 11 of 11	ENSP00000289816.5	Q8N554-2

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.0000193 AC: 3 AN: 155550 AF XY: 0.0000122

Gnomad AFR exome AF: 0.000231

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: 0.0000167

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000186 AC: 26 AN: 1398998 Hom.: 0 Cov.: 33 AF XY: 0.0000130 AC XY: 9 AN XY: 690046

African (AFR) AF: 0.000316 AC: 10 AN: 31602

American (AMR) AF: 0.0000560 AC: 2 AN: 35710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35748

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48882

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5602

European-Non Finnish (NFE) AF: 0.00000927 AC: 10 AN: 1079024

Other (OTH) AF: 0.0000517 AC: 3 AN: 58004

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152204 Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7 AN XY: 74360

African (AFR) AF: 0.000217 AC: 9 AN: 41432

American (AMR) AF: 0.000196 AC: 3 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68042

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000831

ESP6500AA AF: 0.000241 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000249 AC: 2

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	1.1
DANN	Benign	0.70
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.058	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.80
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.090
Sift	Benign	0.45	T
Sift4G	Benign	0.30	T
Polyphen		0.032	B
Vest4		0.065
MVP		0.90
ClinPred		0.044	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.024
gMVP		0.096
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs374649848; hg19: chr16-89805934; COSMIC: COSV57069790; COSMIC: COSV57069790;