4-169991991-T-C

Position:

• chr4-169991991-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_021647.8(MFAP3L):​c.617A>G​(p.Lys206Arg) variant causes a missense change involving the alteration of a 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: MFAP3L NM_021647.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.821

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MFAP3L	NM_021647.8	c.617A>G	p.Lys206Arg	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.617A>G	p.Lys206Arg	missense_variant	3/3	1	NM_021647.8	ENSP00000354583	P1
MFAP3L	ENST00000393704.3	c.308A>G	p.Lys103Arg	missense_variant	2/2	1		ENSP00000377307
	ENST00000508955.2	n.298+1522T>C		intron_variant, non_coding_transcript_variant		3
MFAP3L	ENST00000512698.1	c.308A>G	p.Lys103Arg	missense_variant	2/2	3		ENSP00000422791

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

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

May 18, 2023

The c.617A>G (p.K206R) alteration is located in exon 3 (coding exon 2) of the MFAP3L gene. This alteration results from a A to G substitution at nucleotide position 617, causing the lysine (K) at amino acid position 206 to be replaced by an arginine (R). 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	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	.;T;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.2	.;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.8	N;N;N
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0070	.;D;D
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	.;D;.
Vest4		0.74
MutPred		0.65		.;Loss of methylation at K206 (P = 0.0067);.;
MVP		0.93
MPC		1.1
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.27
gMVP		0.78

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: rs1737741989; hg19: chr4-170913142;