1-39442834-G-T

Variant names:

• chr1-39442834-G-T
• rs587404
• NM_001394062.1:c.19225G>T

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.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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.06
• Publications: 55 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=0.07421109).

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

Sel.	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

Sel.	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.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

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	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	17
DANN	Benign	0.84
DEOGEN2	Benign	0.032	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.013
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.074	T
MetaSVM	Benign	-0.97	T
PhyloP100		1.1
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.066
Sift	Benign	0.49	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
Mutation Taster		=98/2	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

Other links and lift over

dbSNP: rs587404; hg19: chr1-39908506;