6-118905792-A-C

Variant names:

• chr6-118905792-A-C
• rs745312191
• NM_014034.3:c.366A>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_014034.3(ASF1A):​c.366A>C​(p.Leu122Phe) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ASF1A NM_014034.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.05
• Publications: 0 publications found

Genes affected

ASF1A (HGNC:20995): (anti-silencing function 1A histone chaperone) This gene encodes a member of the H3/H4 family of histone chaperone proteins and is similar to the anti-silencing function-1 gene in yeast. The protein is a key component of a histone donor complex that functions in nucleosome assembly. It interacts with histones H3 and H4, and functions together with a chromatin assembly factor during DNA replication and repair. [provided by RefSeq, Jul 2008]

MCM9 (HGNC:21484): (minichromosome maintenance 9 homologous recombination repair factor) The protein encoded by this gene is a member of the mini-chromosome maintenance (MCM) protein family that are essential for the initiation of eukaryotic genome replication. Binding of this protein to chromatin has been shown to be a pre-requisite for recruiting the MCM2-7 helicase to DNA replication origins. This protein also binds, and is a positive regulator of, the chromatin licensing and DNA replication factor 1, CDT1. [provided by RefSeq, Nov 2010]

MCM9 Gene-Disease associations (from GenCC):

• premature ovarian failure 10

  Inheritance: AR, AD Classification: DEFINITIVE, LIMITED Submitted by: Ambry Genetics
• 46,XX ovarian dysgenesis-short stature syndrome

  Inheritance: AR, Unknown Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• male infertility

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014034.3. 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
	ASF1A	NM_014034.3	MANE Select	c.366A>C	p.Leu122Phe	missense	Exon 3 of 4	NP_054753.1	Q9Y294
	MCM9	NM_017696.3	MANE Select	c.1150+5858T>G		intron	N/A	NP_060166.2
	MCM9	NM_001378356.1		c.1150+5858T>G		intron	N/A	NP_001365285.1	Q9NXL9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASF1A	ENST00000229595.6	TSL:1 MANE Select	c.366A>C	p.Leu122Phe	missense	Exon 3 of 4	ENSP00000229595.5	Q9Y294
	MCM9	ENST00000619706.5	TSL:5 MANE Select	c.1150+5858T>G		intron	N/A	ENSP00000480469.1	Q9NXL9-1
	ASF1A	ENST00000877924.1		c.330A>C	p.Leu110Phe	missense	Exon 3 of 4	ENSP00000547983.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000828 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.0036	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.069	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.1
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.48	P
Vest4		0.62
MutPred		0.93		Gain of phosphorylation at T120 (P = 0.1791)
MVP		0.76
MPC		1.5
ClinPred		0.82	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.81
Mutation Taster		=54/46	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: rs745312191; hg19: chr6-119226957;