rs148871932

Positions:

• chr14-45175503-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.2749A>G​(p.Ile917Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,613,004 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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. I917T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0029 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (34 hom.)
• Consequence: FANCM NM_020937.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.116

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=0.0037210584).
• BP6: Variant 14-45175503-A-G is Benign according to our data. Variant chr14-45175503-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 261384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-45175503-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00286 (435/152318) while in subpopulation AMR AF= 0.0206 (315/15290). AF 95% confidence interval is 0.0187. There are 5 homozygotes in gnomad4. There are 253 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCM	NM_020937.4	c.2749A>G	p.Ile917Val	missense_variant	14/23	ENST00000267430.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCM	ENST00000267430.10	c.2749A>G	p.Ile917Val	missense_variant	14/23	1	NM_020937.4	P1

Frequencies

GnomAD3 genomes AF: 0.00285 AC: 434 AN: 152200 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0206

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0154

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00593 AC: 1484 AN: 250232 Hom.: 24 AF XY: 0.00466 AC XY: 631 AN XY: 135292

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.0321

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0161

Gnomad SAS exome AF: 0.000361

Gnomad FIN exome AF: 0.00167

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.00197

GnomAD4 exome AF: 0.00163 AC: 2375 AN: 1460686 Hom.: 34 Cov.: 31 AF XY: 0.00143 AC XY: 1042 AN XY: 726670

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.0317

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0181

Gnomad4 SAS exome AF: 0.000430

Gnomad4 FIN exome AF: 0.00144

Gnomad4 NFE exome AF: 0.0000432

Gnomad4 OTH exome AF: 0.00119

GnomAD4 genome AF: 0.00286 AC: 435 AN: 152318 Hom.: 5 Cov.: 32 AF XY: 0.00340 AC XY: 253 AN XY: 74492

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.0206

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0156

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000842 Hom.: 1

Bravo AF: 0.00426

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00473 AC: 574

Asia WGS AF: 0.00751 AC: 26 AN: 3474

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:3

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 18, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 19, 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

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.038
DANN	Benign	0.23
DEOGEN2	Benign	0.042	T;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0046	N
LIST_S2	Benign	0.36	T;T;T
MetaRNN	Benign	0.0037	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.92	N;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.080	N;N;N
REVEL	Benign	0.0090
Sift	Benign	0.49	T;T;T
Sift4G	Benign	0.96	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.029
MVP		0.15
MPC		0.071
ClinPred		0.00058	T
GERP RS		-1.9
Varity_R		0.019
gMVP		0.092

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: rs148871932; hg19: chr14-45644706;