1-39442834-G-T

Position:

• chr1-39442834-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_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. 13/20 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.06

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MACF1. . Gene score misZ 0.58309 (greater than the threshold 3.09). Trascript score misZ 6.1868 (greater than threshold 3.09). GenCC has associacion of gene with lissencephaly spectrum disorder with complex brainstem malformation, lissencephaly 9 with complex brainstem malformation.
• BP4: Computational evidence support a benign effect (MetaRNN=0.07421109).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MACF1	NM_001394062.1	c.19225G>T	p.Ala6409Ser	missense_variant	78/101	ENST00000564288.6	NP_001380991.1
MACF1	NM_012090.5	c.13048G>T	p.Ala4350Ser	missense_variant	73/93		NP_036222.3
MACF1	NM_001397473.1	c.7303G>T	p.Ala2435Ser	missense_variant	21/41		NP_001384402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MACF1	ENST00000564288.6	c.19225G>T	p.Ala6409Ser	missense_variant	78/101	5	NM_001394062.1	ENSP00000455274.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	17
DANN	Benign	0.84
DEOGEN2	Benign	0.032	T;T;.;T;.
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.013
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.29	T;T;T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.074	T;T;T;T;T
MetaSVM	Benign	-0.97	T
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.010	N;N;N;N;N
REVEL	Benign	0.066
Sift	Benign	0.49	T;T;T;T;T
Sift4G	Benign	0.40	.;.;T;.;.
Polyphen		0.014	.;B;.;.;.
Vest4		0.094
MutPred		0.18		.;Gain of phosphorylation at A6308 (P = 0.0491);.;.;.;
MVP		0.25
ClinPred		0.20	T
GERP RS		5.8
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.016
gMVP		0.071

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: rs587404; hg19: chr1-39908506;