rs754552650

chrX-14864642-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.869T>C(p.Met290Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000197 in 1,208,243 control chromosomes in the GnomAD database, including 1 homozygotes. There are 89 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., 10 hem., cov: 23)
  • Exomes 𝑓: 0.00020 (1 hom. 79 hem.)
• Consequence: FANCB NM_001018113.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.53

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=0.007908583).
• BP6: Variant X-14864642-A-G is Benign according to our data. Variant chrX-14864642-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 368030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000178 (20/112499) while in subpopulation EAS AF= 0.00363 (13/3579). AF 95% confidence interval is 0.00215. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 10 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCB	NM_001018113.3	c.869T>C	p.Met290Thr	missense_variant	3/10	ENST00000650831.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCB	ENST00000650831.1	c.869T>C	p.Met290Thr	missense_variant	3/10		NM_001018113.3	P2

Frequencies

GnomAD3 genomes AF: 0.000178 AC: 20 AN: 112448 Hom.: 0 Cov.: 23 AF XY: 0.000289 AC XY: 10 AN XY: 34590

Gnomad AFR AF: 0.0000323

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00226

Gnomad EAS AF: 0.00362

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: 0.000453 AC: 83 AN: 183393 Hom.: 1 AF XY: 0.000486 AC XY: 33 AN XY: 67859

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00294

Gnomad EAS exome AF: 0.00354

Gnomad SAS exome AF: 0.000367

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000488

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000199 AC: 218 AN: 1095744 Hom.: 1 Cov.: 30 AF XY: 0.000219 AC XY: 79 AN XY: 361164

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00258

Gnomad4 EAS exome AF: 0.00394

Gnomad4 SAS exome AF: 0.000425

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000714

Gnomad4 OTH exome AF: 0.000413

GnomAD4 genome AF: 0.000178 AC: 20 AN: 112499 Hom.: 0 Cov.: 23 AF XY: 0.000289 AC XY: 10 AN XY: 34651

Gnomad4 AFR AF: 0.0000322

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00226

Gnomad4 EAS AF: 0.00363

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000338 Hom.: 3

Bravo AF: 0.000317

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000428 AC: 52

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 10, 2022	- -

VACTERL with hydrocephalus Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

FANCB-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 02, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Fanconi Anemia, X-Linked Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	17
Dann	Benign	0.93
DEOGEN2	Benign	0.41	T;T;T
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.64	T;.;T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.0079	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.4	M;M;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Benign	0.17
Sift	Benign	0.051	T;T;T
Sift4G	Benign	0.063	T;T;T
Polyphen		0.76	P;P;.
Vest4		0.18
MutPred		0.42		Loss of stability (P = 0.0295);Loss of stability (P = 0.0295);Loss of stability (P = 0.0295);
MVP		0.29
MPC		0.25
ClinPred		0.055	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs754552650; hg19: chrX-14882764;