14-45136077-A-T

Variant names:

• chr14-45136077-A-T
• rs755236908
• NM_020937.4:c.46A>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020937.4(FANCM):​c.46A>T​(p.Ile16Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FANCM NM_020937.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00800

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06006378).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCM	NM_020937.4	c.46A>T	p.Ile16Phe	missense_variant	Exon 1 of 23	ENST00000267430.10	NP_065988.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCM	ENST00000267430.10	c.46A>T	p.Ile16Phe	missense_variant	Exon 1 of 23	1	NM_020937.4	ENSP00000267430.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 249750 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135340

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	8.7
DANN	Benign	0.93
DEOGEN2	Benign	0.072	.;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.074	N
LIST_S2	Benign	0.63	T;T;T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.060	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L;L
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Benign	0.068
Sift	Benign	0.037	D;D;D
Sift4G	Benign	0.77	T;T;T
Polyphen		0.047	B;B;.
Vest4		0.15
MutPred		0.17		Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);
MVP		0.12
MPC		0.14
ClinPred		0.22	T
GERP RS		-3.6
Varity_R		0.17
gMVP		0.30

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: rs755236908; hg19: chr14-45605280;