1-39344315-T-C

Variant names:

• chr1-39344315-T-C
• rs7528276
• NM_001394062.1:c.10582-2662T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001394062.1(MACF1):​c.10582-2662T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.936 in 151,210 control chromosomes in the GnomAD database, including 66,504 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.94 (66504 hom., cov: 25)
• Consequence: MACF1 NM_001394062.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.764
• Publications: 2 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.965 is higher than 0.05.

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.10582-2662T>C		intron	N/A	NP_001380991.1	H3BPE1
	MACF1	NM_012090.5		c.4630-5163T>C		intron	N/A	NP_036222.3	Q9UPN3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MACF1	ENST00000564288.6	TSL:5 MANE Select	c.10582-2662T>C		intron	N/A	ENSP00000455274.1	H3BPE1
	MACF1	ENST00000567887.5	TSL:5	c.10693-2662T>C		intron	N/A	ENSP00000455823.1	H3BQK9
	MACF1	ENST00000372915.8	TSL:5	c.10597-2662T>C		intron	N/A	ENSP00000362006.4	A0A7P0MQR8

Frequencies

GnomAD3 genomes AF: 0.937 AC: 141509 AN: 151092 Hom.: 66471 Cov.: 25

Gnomad AFR AF: 0.876

Gnomad AMI AF: 0.961

Gnomad AMR AF: 0.956

Gnomad ASJ AF: 0.949

Gnomad EAS AF: 0.780

Gnomad SAS AF: 0.953

Gnomad FIN AF: 0.986

Gnomad MID AF: 0.869

Gnomad NFE AF: 0.971

Gnomad OTH AF: 0.939

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.936 AC: 141593 AN: 151210 Hom.: 66504 Cov.: 25 AF XY: 0.937 AC XY: 69170 AN XY: 73848

African (AFR) AF: 0.875 AC: 35957 AN: 41080

American (AMR) AF: 0.956 AC: 14544 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.949 AC: 3289 AN: 3464

East Asian (EAS) AF: 0.780 AC: 3973 AN: 5092

South Asian (SAS) AF: 0.953 AC: 4534 AN: 4758

European-Finnish (FIN) AF: 0.986 AC: 10337 AN: 10482

Middle Eastern (MID) AF: 0.870 AC: 254 AN: 292

European-Non Finnish (NFE) AF: 0.971 AC: 65886 AN: 67826

Other (OTH) AF: 0.931 AC: 1946 AN: 2090

Alfa AF: 0.951 Hom.: 8386

Bravo AF: 0.930

Asia WGS AF: 0.821 AC: 2854 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.7
DANN	Benign	0.65
PhyloP100		-0.76
Mutation Taster		=100/0	polymorphism (auto)

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: rs7528276; hg19: chr1-39809987;