rs763653491

Variant names:

• chr14-45154814-T-C
• rs763653491
• NM_020937.4:c.1301T>C
• FANCM p.Ile434Thr

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS1

The NM_020937.4(FANCM):​c.1301T>C​(p.Ile434Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,607,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. I434V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: FANCM NM_020937.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: -0.647
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• FANCM Fanconi-like genomic instability disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Fanconi anemia

  Inheritance: AR Classification: STRONG, SUPPORTIVE, NO_KNOWN Submitted by: ClinGen, Orphanet, G2P
• spermatogenic failure 28

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• male infertility with azoospermia or oligozoospermia due to single gene mutation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary breast carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.021051854).
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000289 (42/1455600) while in subpopulation AMR AF = 0.000946 (42/44414). AF 95% confidence interval is 0.000719. There are 0 homozygotes in GnomAdExome4. There are 17 alleles in the male GnomAdExome4 subpopulation. Median coverage is 28. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020937.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCM	NM_020937.4	MANE Select	c.1301T>C	p.Ile434Thr	missense	Exon 7 of 23	NP_065988.1	Q8IYD8-1
	FANCM	NM_001308133.2		c.1223T>C	p.Ile408Thr	missense	Exon 6 of 22	NP_001295062.1	Q8IYD8-3
	FANCM	NM_001308134.2		c.1301T>C	p.Ile434Thr	missense	Exon 7 of 11	NP_001295063.1	Q8IYD8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCM	ENST00000267430.10	TSL:1 MANE Select	c.1301T>C	p.Ile434Thr	missense	Exon 7 of 23	ENSP00000267430.5	Q8IYD8-1
	FANCM	ENST00000542564.6	TSL:1	c.1223T>C	p.Ile408Thr	missense	Exon 6 of 22	ENSP00000442493.2	Q8IYD8-3
	FANCM	ENST00000556250.6	TSL:1	c.1301T>C	p.Ile434Thr	missense	Exon 7 of 22	ENSP00000452033.2	H0YJS3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000156 AC: 39 AN: 250124 AF XY: 0.000104

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00111

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000289 AC: 42 AN: 1455600 Hom.: 0 Cov.: 28 AF XY: 0.0000235 AC XY: 17 AN XY: 724298

African (AFR) AF: 0.00 AC: 0 AN: 33386

American (AMR) AF: 0.000946 AC: 42 AN: 44414

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26024

East Asian (EAS) AF: 0.00 AC: 0 AN: 39394

South Asian (SAS) AF: 0.00 AC: 0 AN: 85560

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53206

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5436

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108112

Other (OTH) AF: 0.00 AC: 0 AN: 60068

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74364

African (AFR) AF: 0.00 AC: 0 AN: 41468

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000452 Hom.: 0

Bravo AF: 0.0000416

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Fanconi anemia (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	Spermatogenic failure 28;C4748170:Premature ovarian failure 15 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	5.6
DANN	Benign	0.66
DEOGEN2	Benign	0.072	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.021	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.65
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.040
Sift	Benign	0.56	T
Sift4G	Benign	0.38	T
PromoterAI		-0.0072	Neutral
Varity_R		0.047
gMVP		0.20
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs763653491;

hg19: chr14-45624017;