Genetic Variant MACF1:p.Ala6409Ser (chr1-39442834-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001394062.1(MACF1):c.19225G>T(p.Ala6409Ser) 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. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A6409T) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Consequence

MACF1
NM_001394062.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.06

Publications

55 publications found

Variant links:

Genes affected

MACF1 (HGNC:13664): (microtubule actin crosslinking factor 1) This gene encodes a large protein containing numerous spectrin and leucine-rich repeat (LRR) domains. The encoded protein is a member of a family of proteins that form bridges between different cytoskeletal elements. This protein facilitates actin-microtubule interactions at the cell periphery and couples the microtubule network to cellular junctions. Alternative splicing results in multiple transcript variants, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, May 2013]

MACF1 Gene-Disease associations (from GenCC):

lissencephaly 9 with complex brainstem malformation
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
lissencephaly spectrum disorder with complex brainstem malformation
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
autosomal dominant nonsyndromic hearing loss
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

MACF1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07421109).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001394062.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MACF1	NM_001394062.1	MANE Select	c.19225G>T	p.Ala6409Ser	missense	Exon 78 of 101	NP_001380991.1	H3BPE1
MACF1	NM_012090.5		c.13048G>T	p.Ala4350Ser	missense	Exon 73 of 93	NP_036222.3	Q9UPN3-2
MACF1	NM_001397473.1		c.7303G>T	p.Ala2435Ser	missense	Exon 21 of 41	NP_001384402.1	O94854-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MACF1	ENST00000564288.6	TSL:5 MANE Select	c.19225G>T	p.Ala6409Ser	missense	Exon 78 of 101	ENSP00000455274.1	H3BPE1
MACF1	ENST00000567887.5	TSL:5	c.19336G>T	p.Ala6446Ser	missense	Exon 78 of 101	ENSP00000455823.1	H3BQK9
MACF1	ENST00000372915.8	TSL:5	c.18913G>T	p.Ala6305Ser	missense	Exon 76 of 96	ENSP00000362006.4	A0A7P0MQR8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.032

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.013

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.29

M_CAP

Benign

0.013

MetaRNN

Benign

0.074

MetaSVM

Benign

-0.97

PhyloP100

1.1

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.010

REVEL

Benign

0.066

Sift

Benign

0.49

Sift4G

Benign

0.40

Polyphen

0.014

Vest4

0.094

MutPred

0.18

Gain of phosphorylation at A6308 (P = 0.0491)

MVP

0.25

ClinPred

0.20

GERP RS

5.8

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.7

Varity_R

0.016

gMVP

0.071

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over