4-169991760-C-T

Position:

• chr4-169991760-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_021647.8(MFAP3L):​c.848G>A​(p.Arg283Lys) 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 benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MFAP3L NM_021647.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.183

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]

ENSG00000249955 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.035128236).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MFAP3L	NM_021647.8	c.848G>A	p.Arg283Lys	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.848G>A	p.Arg283Lys	missense_variant	3/3	1	NM_021647.8	ENSP00000354583.3
MFAP3L	ENST00000393704.3	c.539G>A	p.Arg180Lys	missense_variant	2/2	1		ENSP00000377307.3
ENSG00000249955	ENST00000508955.2	n.298+1291C>T		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251110 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135696

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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

Jul 10, 2024

The c.848G>A (p.R283K) alteration is located in exon 3 (coding exon 2) of the MFAP3L gene. This alteration results from a G to A substitution at nucleotide position 848, causing the arginine (R) at amino acid position 283 to be replaced by a lysine (K). 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	Benign	0.070
BayesDel_addAF	Benign	-0.0019	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	8.7
DANN	Benign	0.64
DEOGEN2	Benign	0.015	.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.62	T;T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.035	T;T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	0.34	.;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.10	N;N
REVEL	Benign	0.27
Sift	Benign	0.48	.;T
Sift4G	Benign	0.93	T;T
Polyphen		0.020	.;B
Vest4		0.075
MutPred		0.31		.;Gain of glycosylation at Y287 (P = 2e-04);
MVP		0.27
MPC		0.40
ClinPred		0.051	T
GERP RS		3.8
Varity_R		0.055
gMVP		0.29

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

LitVar

Other links and lift over

dbSNP: rs755391499; hg19: chr4-170912911;