rs143976596

chrX-14850608-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001018113.3(FANCB):c.1393T>C(p.Ser465Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000735 in 1,183,603 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 23 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/17 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. S465T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., 11 hem., cov: 23)
  • Exomes 𝑓: 0.000046 (0 hom. 12 hem.)
• Consequence: FANCB NM_001018113.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.71

Genes affected

FANCB (HGNC:3583): (FA complementation group B) This gene encodes a member of the Fanconi anemia complementation group B. This protein is assembled into a nucleoprotein complex that is involved in the repair of DNA lesions. Mutations in this gene can cause chromosome instability and VACTERL syndrome with hydrocephalus. [provided by RefSeq, Apr 2016]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0062371194).
• BP6: Variant X-14850608-A-G is Benign according to our data. Variant chrX-14850608-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 526453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000342 (38/111148) while in subpopulation AFR AF= 0.00111 (34/30548). AF 95% confidence interval is 0.000818. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 11 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCB	NM_001018113.3	c.1393T>C	p.Ser465Pro	missense_variant	7/10	ENST00000650831.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCB	ENST00000650831.1	c.1393T>C	p.Ser465Pro	missense_variant	7/10		NM_001018113.3	P2

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 38 AN: 111096 Hom.: 0 Cov.: 23 AF XY: 0.000331 AC XY: 11 AN XY: 33264

Gnomad AFR AF: 0.00112

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000385

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000120 AC: 22 AN: 182670 Hom.: 0 AF XY: 0.000104 AC XY: 7 AN XY: 67232

Gnomad AFR exome AF: 0.00122

Gnomad AMR exome AF: 0.000147

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000245

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000457 AC: 49 AN: 1072455 Hom.: 0 Cov.: 26 AF XY: 0.0000353 AC XY: 12 AN XY: 340413

Gnomad4 AFR exome AF: 0.00104

Gnomad4 AMR exome AF: 0.000228

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000332

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000489

Gnomad4 OTH exome AF: 0.000177

GnomAD4 genome AF: 0.000342 AC: 38 AN: 111148 Hom.: 0 Cov.: 23 AF XY: 0.000330 AC XY: 11 AN XY: 33326

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.000384

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000680 Hom.: 0

Bravo AF: 0.000521

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000115 AC: 14

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Fanconi anemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 19, 2021

- -

Fanconi anemia complementation group B;C2931228:VACTERL association, X-linked, with or without hydrocephalus Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.98
Cadd	Benign	0.036
Dann	Benign	0.72
DEOGEN2	Benign	0.094	T;T;T
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.49	T;.;T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.0062	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.12	N;N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.13	N;N;N
REVEL	Benign	0.018
Sift	Benign	0.33	T;T;T
Sift4G	Benign	0.40	T;T;T
Polyphen		0.0090	B;B;.
Vest4		0.11
MVP		0.068
MPC		0.13
ClinPred		0.0093	T
GERP RS		-8.8
Varity_R		0.086

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

Publications

LitVar

Other links and lift over

dbSNP: rs143976596; hg19: chrX-14868730;