NM_020937.4:c.3547T>C

Variant names:

• chr14-45176301-T-C
• rs142667852
• NM_020937.4:c.3547T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4 BP6_Very_Strong BP7 BS1 BS2

The NM_020937.4(FANCM):​c.3547T>C​(p.Leu1183Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000538 in 1,614,082 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (1 hom.)
• Consequence: FANCM NM_020937.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.81
• 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: G2P, Orphanet, ClinGen
• 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.221).
• BP6: Variant 14-45176301-T-C is Benign according to our data. Variant chr14-45176301-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 414851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.81 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00307 (467/152312) while in subpopulation AFR AF = 0.0108 (451/41576). AF 95% confidence interval is 0.01. There are 4 homozygotes in GnomAd4. There are 227 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

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.3547T>C	p.Leu1183Leu	synonymous	Exon 14 of 23	NP_065988.1	Q8IYD8-1
	FANCM	NM_001308133.2		c.3469T>C	p.Leu1157Leu	synonymous	Exon 13 of 22	NP_001295062.1	Q8IYD8-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCM	ENST00000267430.10	TSL:1 MANE Select	c.3547T>C	p.Leu1183Leu	synonymous	Exon 14 of 23	ENSP00000267430.5	Q8IYD8-1
	FANCM	ENST00000542564.6	TSL:1	c.3469T>C	p.Leu1157Leu	synonymous	Exon 13 of 22	ENSP00000442493.2	Q8IYD8-3
	FANCM	ENST00000556250.6	TSL:1	c.3340T>C	p.Leu1114Leu	synonymous	Exon 13 of 22	ENSP00000452033.2	H0YJS3

Frequencies

GnomAD3 genomes AF: 0.00306 AC: 465 AN: 152194 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0108

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

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: 0.0000294

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000730 AC: 183 AN: 250736 AF XY: 0.000626

Gnomad AFR exome AF: 0.00989

Gnomad AMR exome AF: 0.000665

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: 0.000328

GnomAD4 exome AF: 0.000274 AC: 401 AN: 1461770 Hom.: 1 Cov.: 33 AF XY: 0.000217 AC XY: 158 AN XY: 727196

African (AFR) AF: 0.00935 AC: 313 AN: 33480

American (AMR) AF: 0.000693 AC: 31 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53360

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111972

Other (OTH) AF: 0.000712 AC: 43 AN: 60394

GnomAD4 genome AF: 0.00307 AC: 467 AN: 152312 Hom.: 4 Cov.: 32 AF XY: 0.00305 AC XY: 227 AN XY: 74482

African (AFR) AF: 0.0108 AC: 451 AN: 41576

American (AMR) AF: 0.000784 AC: 12 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68012

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00136 Hom.: 1

Bravo AF: 0.00334

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	FANCM-related disorder (1)
-	-	1	Fanconi anemia (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)
-	-	1	Premature ovarian failure 15 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	7.2
DANN	Benign	0.72
PhyloP100		1.8
PromoterAI		0.014	Neutral
Mutation Taster		=100/0	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: rs142667852; hg19: chr14-45645504;