Genetic Variant MFAP4:p.Val68Ala (chr17-19386347-A-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_002404.3(MFAP4):c.203T>C(p.Val68Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000744 in 1,612,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

MFAP4
NM_002404.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.57

Variant links:

Genes affected

MFAP4 (HGNC:7035): (microfibril associated protein 4) This gene encodes a protein with similarity to a bovine microfibril-associated protein. The protein has binding specificities for both collagen and carbohydrate. It is thought to be an extracellular matrix protein which is involved in cell adhesion or intercellular interactions. The gene is located within the Smith-Magenis syndrome region. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2010]

MFAP4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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, 0.899

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MFAP4	NM_002404.3 link	c.203T>C	p.Val68Ala	missense_variant	Exon 3 of 6	ENST00000299610.5	NP_002395.1	P55083-1
MFAP4	NM_001198695.2 link	c.275T>C	p.Val92Ala	missense_variant	Exon 3 of 6		NP_001185624.1	P55083-2A0A024QZ34

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MFAP4	ENST00000299610.5 link	c.203T>C	p.Val68Ala	missense_variant	Exon 3 of 6	1	NM_002404.3	ENSP00000299610.5	P55083-1
MFAP4	ENST00000497081.6 link	c.278T>C	p.Val93Ala	missense_variant	Exon 2 of 5	1		ENSP00000468578.1	K7ES70
MFAP4	ENST00000395592.6 link	c.275T>C	p.Val92Ala	missense_variant	Exon 3 of 6	1		ENSP00000378957.2	P55083-2
MFAP4	ENST00000571210.1 link	n.238T>C		non_coding_transcript_exon_variant	Exon 3 of 5	5

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152036

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1460378

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

726454

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000990

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152036

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74260

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000312

Hom.:

Bravo

AF:

0.00000378

EpiCase

AF:

0.00

EpiControl

AF:

0.0000594

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.275T>C (p.V92A) alteration is located in exon 3 (coding exon 3) of the MFAP4 gene. This alteration results from a T to C substitution at nucleotide position 275, causing the valine (V) at amino acid position 92 to be replaced by an alanine (A). 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

0.44

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

T;.;T

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.78

T;T;T

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.90

D;D;D

MetaSVM

Uncertain

0.44

MutationAssessor

Benign

1.9

.;.;L

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-3.4

.;D;D

REVEL

Pathogenic

0.81

Sift

Uncertain

0.024

.;D;D

Sift4G

Benign

0.062

T;T;D

Polyphen

0.99

.;.;D

Vest4

0.87

MutPred

0.72

.;.;Gain of sheet (P = 0.1945);

MVP

0.80

MPC

1.3

ClinPred

0.99

GERP RS

5.3

Varity_R

0.32

gMVP

0.72

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over