chr2-58159770-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_018062.4(FANCL):c.1123C>G(p.His375Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,612,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H375P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

FANCL
NM_018062.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.374

Variant links:

Genes affected

FANCL (HGNC:20748): (FA complementation group L) This gene encodes a ubiquitin ligase that is a member of the Fanconi anemia complementation group (FANC). Members of this group are related by their assembly into a common nuclear protein complex rather than by sequence similarity. This gene encodes the protein for complementation group L that mediates monoubiquitination of FANCD2 as well as FANCI. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2018]

FANCL links:

VRK2 (HGNC:12719): (VRK serine/threonine kinase 2) This gene encodes a member of the vaccinia-related kinase (VRK) family of serine/threonine protein kinases. The encoded protein acts as an effector of signaling pathways that regulate apoptosis and tumor cell growth. Variants in this gene have been associated with schizophrenia. Alternative splicing results in multiple transcript variants that differ in their subcellular localization and biological activity. [provided by RefSeq, Jan 2014]

VRK2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.052068412).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCL	NM_018062.4 link	c.1123C>G	p.His375Asp	missense_variant	Exon 14 of 14	ENST00000233741.9	NP_060532.2
VRK2	NM_006296.7 link	c.*77G>C		3_prime_UTR_variant	Exon 13 of 13	ENST00000340157.9	NP_006287.2	Q86Y07-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCL	ENST00000233741.9 link	c.1123C>G	p.His375Asp	missense_variant	Exon 14 of 14	1	NM_018062.4	ENSP00000233741.5		Q9NW38-1
VRK2	ENST00000340157.9 link	c.*77G>C		3_prime_UTR_variant	Exon 13 of 13	1	NM_006296.7	ENSP00000342381.4		Q86Y07-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151962

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD2 exomes

AF:

0.00000401

AC:

AN:

249236

AF XY:

0.00000740

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00000889

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1460996

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726790

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

33454

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

44670

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26102

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39652

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

86180

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

53152

Gnomad4 NFE exome

AF:

0.00000180

AC:

AN:

1111662

Gnomad4 Remaining exome

AF:

0.00

AC:

AN:

60362

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151962

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74200

show subpopulations

Gnomad4 AFR

AF:

0.00

AC:

AN:

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000147

AC:

0.0000147184

AN:

0.0000147184

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000468

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Fanconi anemia

Uncertain:1

May 04, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 375 of the FANCL protein (p.His375Asp). This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with FANCL-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.011

T;T;.;T

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.70

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.51

T;T;T;T

M_CAP

Benign

0.021

MetaRNN

Benign

0.052

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

.;N;.;.

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.080

N;N;N;N

REVEL

Benign

0.029

Sift

Uncertain

0.028

D;D;D;D

Sift4G

Uncertain

0.051

T;D;D;D

Polyphen

0.0

B;B;B;.

Vest4

0.25

MutPred

0.26

.;Loss of methylation at R373 (P = 0.0391);.;.;

MVP

0.24

MPC

0.031

ClinPred

0.22

GERP RS

-0.55

Varity_R

0.046

gMVP

0.47

Mutation Taster

=95/5

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over