MACF1 p.Phe7502Leu

Variant names:

• chr1-39485632-T-A
• NM_001394062.1:c.22506T>A
• MACF1 p.Phe7502Leu

Your query was ambiguous. Multiple possible variants found:

• chr1-39485632-T-A
• chr1-39485632-T-G
• chr1-39485630-T-C
• chr1-39485630-TTT-CTC
• chr1-39485630-TTT-CTA
• chr1-39485630-TTT-CTG

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001394062.1(MACF1):​c.22506T>A​(p.Phe7502Leu) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F7502S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MACF1 NM_001394062.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0620
• Publications: 0 publications found

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

ACMG classification

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=0.1971612).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MACF1	NM_001394062.1	MANE Select	c.22506T>A	p.Phe7502Leu	missense	Exon 101 of 101	NP_001380991.1	H3BPE1
	MACF1	NM_012090.5		c.16131T>A	p.Phe5377Leu	missense	Exon 93 of 93	NP_036222.3	Q9UPN3-2
	MACF1	NM_001397473.1		c.10386T>A	p.Phe3462Leu	missense	Exon 41 of 41	NP_001384402.1	O94854-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MACF1	ENST00000564288.6	TSL:5 MANE Select	c.22506T>A	p.Phe7502Leu	missense	Exon 101 of 101	ENSP00000455274.1	H3BPE1
	MACF1	ENST00000497807.1	TSL:1	n.1334T>A		non_coding_transcript_exon	Exon 3 of 3
	MACF1	ENST00000567887.5	TSL:5	c.22617T>A	p.Phe7539Leu	missense	Exon 101 of 101	ENSP00000455823.1	H3BQK9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Benign	0.046
Eigen_PC	Benign	0.064
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.74	T
PhyloP100		-0.062
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.2	D
REVEL	Benign	0.26
Sift	Benign	0.070	T
Sift4G	Uncertain	0.0020	D
Varity_R		0.32
gMVP		0.19
Mutation Taster		=92/8	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr1-39951304;