rs1800338

Variant names:

• chr16-89775812-T-C
• rs1800338
• NM_000135.4:c.1830A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000135.4(FANCA):​c.1830A>G​(p.Ala610Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00237 in 1,609,898 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (5 hom.)
• Consequence: FANCA NM_000135.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.215
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 16-89775812-T-C is Benign according to our data. Variant chr16-89775812-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 237037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.215 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00196 (299/152302) while in subpopulation NFE AF = 0.00335 (228/68026). AF 95% confidence interval is 0.00299. There are 1 homozygotes in GnomAd4. There are 136 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 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.1830A>G	p.Ala610Ala	synonymous	Exon 21 of 43	NP_000126.2	O15360-1
	FANCA	NM_001286167.3		c.1830A>G	p.Ala610Ala	synonymous	Exon 21 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.1830A>G	p.Ala610Ala	synonymous	Exon 21 of 43	ENSP00000373952.3	O15360-1
	FANCA	ENST00000567205.2	TSL:1	n.1830A>G		non_coding_transcript_exon	Exon 21 of 27	ENSP00000457027.2	H3BT53
	FANCA	ENST00000564475.6	TSL:2	c.1830A>G	p.Ala610Ala	synonymous	Exon 21 of 42	ENSP00000454977.2	H3BNS0

Frequencies

GnomAD3 genomes AF: 0.00196 AC: 299 AN: 152184 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00335

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00174 AC: 430 AN: 247414 AF XY: 0.00183

Gnomad AFR exome AF: 0.00101

Gnomad AMR exome AF: 0.000586

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00131

Gnomad NFE exome AF: 0.00305

Gnomad OTH exome AF: 0.000825

GnomAD4 exome AF: 0.00241 AC: 3511 AN: 1457596 Hom.: 5 Cov.: 29 AF XY: 0.00232 AC XY: 1683 AN XY: 724964

African (AFR) AF: 0.000599 AC: 20 AN: 33394

American (AMR) AF: 0.000653 AC: 29 AN: 44424

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26010

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.000549 AC: 47 AN: 85688

European-Finnish (FIN) AF: 0.00131 AC: 70 AN: 53264

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5760

European-Non Finnish (NFE) AF: 0.00289 AC: 3209 AN: 1109180

Other (OTH) AF: 0.00214 AC: 129 AN: 60216

GnomAD4 genome AF: 0.00196 AC: 299 AN: 152302 Hom.: 1 Cov.: 32 AF XY: 0.00183 AC XY: 136 AN XY: 74476

African (AFR) AF: 0.000602 AC: 25 AN: 41562

American (AMR) AF: 0.00177 AC: 27 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4828

European-Finnish (FIN) AF: 0.000942 AC: 10 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00335 AC: 228 AN: 68026

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00222 Hom.: 1

Bravo AF: 0.00182

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	Fanconi anemia (3)
-	-	3	Fanconi anemia complementation group A (3)
-	-	3	not specified (3)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	4.7
DANN	Benign	0.64
PhyloP100		-0.21
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs1800338; hg19: chr16-89842220;