chr14-45188821-C-T

Position:

chr14-45188821-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000267430.10(FANCM):c.4799C>T(p.Thr1600Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0192 in 1,611,134 control chromosomes in the GnomAD database, including 399 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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. T1600A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.015 ( 25 hom., cov: 32)

Exomes 𝑓: 0.020 ( 374 hom. )

Consequence

FANCM
ENST00000267430.10 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 1.30

Variant links:

Genes affected

FANCM (HGNC:23168): (FA complementation group M) 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 M. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

FANCM links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0061993003).

BP6

Variant 14-45188821-C-T is Benign according to our data. Variant chr14-45188821-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 218780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-45188821-C-T is described in Lovd as [Benign]. Variant chr14-45188821-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0154 (2346/152068) while in subpopulation NFE AF= 0.0224 (1522/68008). AF 95% confidence interval is 0.0214. There are 25 homozygotes in gnomad4. There are 1170 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCM	NM_020937.4 linkuse as main transcript	c.4799C>T	p.Thr1600Ile	missense_variant	20/23	ENST00000267430.10	NP_065988.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCM	ENST00000267430.10 linkuse as main transcript	c.4799C>T	p.Thr1600Ile	missense_variant	20/23	1	NM_020937.4	ENSP00000267430	P1	Q8IYD8-1

Frequencies

GnomAD3 genomes

AF:

0.0154

AC:

2347

AN:

151950

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00307

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.00733

Gnomad ASJ

AF:

0.0265

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.0439

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0224

Gnomad OTH

AF:

0.00860

GnomAD3 exomes

AF:

0.0176

AC:

4391

AN:

250098

Hom.:

AF XY:

0.0172

AC XY:

2328

AN XY:

135288

show subpopulations

Gnomad AFR exome

AF:

0.00285

Gnomad AMR exome

AF:

0.00743

Gnomad ASJ exome

AF:

0.0241

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00177

Gnomad FIN exome

AF:

0.0429

Gnomad NFE exome

AF:

0.0245

Gnomad OTH exome

AF:

0.0169

GnomAD4 exome

AF:

0.0196

AC:

28572

AN:

1459066

Hom.:

374

Cov.:

AF XY:

0.0193

AC XY:

14031

AN XY:

726008

show subpopulations

Gnomad4 AFR exome

AF:

0.00305

Gnomad4 AMR exome

AF:

0.00734

Gnomad4 ASJ exome

AF:

0.0240

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00175

Gnomad4 FIN exome

AF:

0.0427

Gnomad4 NFE exome

AF:

0.0217

Gnomad4 OTH exome

AF:

0.0157

GnomAD4 genome

AF:

0.0154

AC:

2346

AN:

152068

Hom.:

Cov.:

AF XY:

0.0157

AC XY:

1170

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.00306

Gnomad4 AMR

AF:

0.00726

Gnomad4 ASJ

AF:

0.0265

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00208

Gnomad4 FIN

AF:

0.0439

Gnomad4 NFE

AF:

0.0224

Gnomad4 OTH

AF:

0.00851

Alfa

AF:

0.0207

Hom.:

Bravo

AF:

0.0125

TwinsUK

AF:

0.0208

AC:

ALSPAC

AF:

0.0213

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.0244

AC:

210

ExAC

AF:

0.0182

AC:

2204

Asia WGS

AF:

0.00173

AC:

AN:

3474

EpiCase

AF:

0.0186

EpiControl

AF:

0.0182

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The FANCM p.Thr1600Ile variant was identified in 20 of 1034 proband chromosomes (frequency: 0.019) from individuals or families with breast or ovarian cancer (Garcia_2009_PMID:19737859; Nguyen-Dumont_2018_PMID:29351780). The variant was identified in dbSNP (ID: rs61746943) and ClinVar (classified as benign by Invitae and Division of Genomic Diagnostics, The Children's Hospital of Philadelphia and as likely benign by Illumina). The variant was identified in control databases in 4968 of 281464 chromosomes (75 homozygous) at a frequency of 0.01765 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 1071 of 25094 chromosomes (freq: 0.04268), European (non-Finnish) in 3124 of 128208 chromosomes (freq: 0.02437), Ashkenazi Jewish in 250 of 10330 chromosomes (freq: 0.0242), Other in 134 of 7176 chromosomes (freq: 0.01867), Latino in 260 of 35298 chromosomes (freq: 0.007366), African in 75 of 24870 chromosomes (freq: 0.003016) and South Asian in 54 of 30558 chromosomes (freq: 0.001767), but was not observed in the East Asian population. The p.Thr1600 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Mar 25, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 27, 2021	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 15, 2021	- -

Premature ovarian failure 15

Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Fanconi anemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

T;.;.

Eigen

Benign

-0.0098

Eigen_PC

Benign

-0.048

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.80

T;T;T

MetaRNN

Benign

0.0062

T;T;T

MetaSVM

Benign

-0.80

MutationAssessor

Uncertain

2.4

M;.;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-3.6

D;D;D

REVEL

Benign

0.26

Sift

Uncertain

0.0070

D;D;D

Sift4G

Uncertain

0.014

D;D;D

Polyphen

0.93

P;.;.

Vest4

0.11

MPC

0.31

ClinPred

0.018

GERP RS

2.7

Varity_R

0.13

gMVP

0.28

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