chr4-169991933-G-T

Position:

• chr4-169991933-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_021647.8(MFAP3L):​c.675C>A​(p.Phe225Leu) variant causes a missense change. 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: MFAP3L NM_021647.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.08

Genes affected

MFAP3L (HGNC:29083): (microfibril associated protein 3 like) Located in several cellular components, including cell junction; nucleoplasm; and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.908

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MFAP3L	NM_021647.8	c.675C>A	p.Phe225Leu	missense_variant	3/3	ENST00000361618.4	NP_067679.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MFAP3L	ENST00000361618.4	c.675C>A	p.Phe225Leu	missense_variant	3/3	1	NM_021647.8	ENSP00000354583	P1
MFAP3L	ENST00000393704.3	c.366C>A	p.Phe122Leu	missense_variant	2/2	1		ENSP00000377307
	ENST00000508955.2	n.298+1464G>T		intron_variant, non_coding_transcript_variant		3
MFAP3L	ENST00000512698.1	c.366C>A	p.Phe122Leu	missense_variant	2/2	3		ENSP00000422791

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 12, 2023

The c.675C>A (p.F225L) alteration is located in exon 3 (coding exon 2) of the MFAP3L gene. This alteration results from a C to A substitution at nucleotide position 675, causing the phenylalanine (F) at amino acid position 225 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	.;T;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.2	.;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.2	D;D;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.011	.;D;D
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	.;D;.
Vest4		0.84
MutPred		0.80		.;Gain of glycosylation at T223 (P = 0.0093);.;
MVP		0.84
MPC		1.3
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.44
gMVP		0.91

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-170913084;