14-45154735-G-T

Variant names:

• chr14-45154735-G-T
• rs199929558
• NM_020937.4:c.1222G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_020937.4(FANCM):​c.1222G>T​(p.Asp408Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000689 in 1,451,156 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D408G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: FANCM NM_020937.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.97
• 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):

• Fanconi anemia

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: G2P, Orphanet
• 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
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCM	NM_020937.4	MANE Select	c.1222G>T	p.Asp408Tyr	missense	Exon 7 of 23	NP_065988.1
	FANCM	NM_001308133.2		c.1144G>T	p.Asp382Tyr	missense	Exon 6 of 22	NP_001295062.1
	FANCM	NM_001308134.2		c.1222G>T	p.Asp408Tyr	missense	Exon 7 of 11	NP_001295063.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCM	ENST00000267430.10	TSL:1 MANE Select	c.1222G>T	p.Asp408Tyr	missense	Exon 7 of 23	ENSP00000267430.5
	FANCM	ENST00000542564.6	TSL:1	c.1144G>T	p.Asp382Tyr	missense	Exon 6 of 22	ENSP00000442493.2
	FANCM	ENST00000556250.6	TSL:1	c.1222G>T	p.Asp408Tyr	missense	Exon 7 of 22	ENSP00000452033.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451156 Hom.: 0 Cov.: 27 AF XY: 0.00000138 AC XY: 1 AN XY: 722192

African (AFR) AF: 0.00 AC: 0 AN: 33326

American (AMR) AF: 0.00 AC: 0 AN: 44430

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25994

East Asian (EAS) AF: 0.00 AC: 0 AN: 39342

South Asian (SAS) AF: 0.00 AC: 0 AN: 84846

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53048

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5544

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1104724

Other (OTH) AF: 0.00 AC: 0 AN: 59902

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.0
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Benign	0.18
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.024	D
Polyphen		0.53	P
Vest4		0.61
MutPred		0.48		Gain of catalytic residue at L403 (P = 2e-04)
MVP		0.65
MPC		0.11
ClinPred		0.95	D
GERP RS		3.5
PromoterAI		-0.060	Neutral
Varity_R		0.67
gMVP		0.56
Mutation Taster		=88/12	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

Other links and lift over

dbSNP: rs199929558; hg19: chr14-45623938;