rs116519044

chr14-45176617-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_020937.4(FANCM):c.3863A>G(p.Asn1288Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,609,998 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0086 (18 hom., cov: 32)
  • Exomes 𝑓: 0.00094 (19 hom.)
• Consequence: FANCM NM_020937.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.54

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028741062).
• BP6: Variant 14-45176617-A-G is Benign according to our data. Variant chr14-45176617-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 210989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-45176617-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00858 (1306/152278) while in subpopulation AFR AF= 0.0299 (1243/41548). AF 95% confidence interval is 0.0285. There are 18 homozygotes in gnomad4. There are 591 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCM	NM_020937.4	c.3863A>G	p.Asn1288Ser	missense_variant	14/23	ENST00000267430.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCM	ENST00000267430.10	c.3863A>G	p.Asn1288Ser	missense_variant	14/23	1	NM_020937.4	P1

Frequencies

GnomAD3 genomes AF: 0.00854 AC: 1300 AN: 152160 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0299

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00227 AC: 561 AN: 247188 Hom.: 7 AF XY: 0.00146 AC XY: 195 AN XY: 133430

Gnomad AFR exome AF: 0.0306

Gnomad AMR exome AF: 0.00130

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: 0.000134

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000935 AC: 1363 AN: 1457720 Hom.: 19 Cov.: 32 AF XY: 0.000806 AC XY: 584 AN XY: 724882

Gnomad4 AFR exome AF: 0.0316

Gnomad4 AMR exome AF: 0.00152

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000587

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000973

Gnomad4 OTH exome AF: 0.00193

GnomAD4 genome AF: 0.00858 AC: 1306 AN: 152278 Hom.: 18 Cov.: 32 AF XY: 0.00794 AC XY: 591 AN XY: 74476

Gnomad4 AFR AF: 0.0299

Gnomad4 AMR AF: 0.00262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00148 Hom.: 7

Bravo AF: 0.00954

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0266 AC: 117

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00264 AC: 321

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 01, 2020	- -

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

Invitae

Feb 01, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.79
Cadd	Benign	0.71
Dann	Benign	0.22
DEOGEN2	Benign	0.067	T;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.70	T;T;T
MetaRNN	Benign	0.0029	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.53	N;N;N
REVEL	Benign	0.073
Sift	Benign	0.66	T;T;T
Sift4G	Benign	0.81	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.010
MVP		0.25
MPC		0.068
ClinPred		0.0033	T
GERP RS		3.7
Varity_R		0.025
gMVP		0.12

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

Other links and lift over

dbSNP: rs116519044; hg19: chr14-45645820; COSMIC: COSV57506755; COSMIC: COSV57506755;