13-113064419-C-A

Variant names:

• chr13-113064419-C-A
• rs376533695
• NM_001112732.3:c.605C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001112732.3(MCF2L):​c.605C>A​(p.Thr202Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,548 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. T202M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MCF2L NM_001112732.3 missense, splice_region
• Scores: Splicing: ADA: 0.8971
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.30
• Publications: 0 publications found

Genes affected

MCF2L (HGNC:14576): (MCF.2 cell line derived transforming sequence like) This gene encodes a guanine nucleotide exchange factor that interacts specifically with the GTP-bound Rac1 and plays a role in the Rho/Rac signaling pathways. A variant in this gene was associated with osteoarthritis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.825

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001112732.3. 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
	MCF2L	NM_001112732.3	MANE Select	c.605C>A	p.Thr202Lys	missense splice_region	Exon 6 of 30	NP_001106203.2	O15068-9
	MCF2L	NM_001438390.1		c.704C>A	p.Thr235Lys	missense splice_region	Exon 6 of 32	NP_001425319.1
	MCF2L	NM_001438391.1		c.695C>A	p.Thr232Lys	missense splice_region	Exon 7 of 33	NP_001425320.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCF2L	ENST00000535094.7	TSL:2 MANE Select	c.605C>A	p.Thr202Lys	missense splice_region	Exon 6 of 30	ENSP00000440374.2	O15068-9
	MCF2L	ENST00000421756.5	TSL:1	c.617C>A	p.Thr206Lys	missense splice_region	Exon 6 of 28	ENSP00000397285.1	O15068-3
	MCF2L	ENST00000375597.8	TSL:1	c.599C>A	p.Thr200Lys	missense splice_region	Exon 6 of 27	ENSP00000364747.4	O15068-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453548 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 723552

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33354

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26082

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.00 AC: 0 AN: 86134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51112

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1106560

Other (OTH) AF: 0.00 AC: 0 AN: 60194

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.097	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-0.53	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		7.3
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.97	D
Vest4		0.93
MVP		0.89
MPC		0.78
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.74
gMVP		0.78
Mutation Taster		=57/43	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.90
dbscSNV1_RF	Benign	0.69
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: rs376533695; hg19: chr13-113718733;