chr1-39092100-T-C

Variant names:

• chr1-39092100-T-C
• rs260964
• ENST00000567887.5:c.220+7662T>C

Variant summary

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

The NM_012090.5(MACF1):​c.220+7662T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.686 in 152,058 control chromosomes in the GnomAD database, including 36,853 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 0.69 (36853 hom., cov: 31)
• Consequence: MACF1 NM_012090.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.661
• 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.968 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012090.5. 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_012090.5		c.220+7662T>C		intron	N/A	NP_036222.3	Q9UPN3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MACF1	ENST00000567887.5	TSL:5	c.220+7662T>C		intron	N/A	ENSP00000455823.1	H3BQK9
	MACF1	ENST00000372915.8	TSL:5	c.220+7662T>C		intron	N/A	ENSP00000362006.4	A0A7P0MQR8
	MACF1	ENST00000361689.7	TSL:5	c.220+7662T>C		intron	N/A	ENSP00000354573.2	Q9UPN3-2

Frequencies

GnomAD3 genomes AF: 0.687 AC: 104317 AN: 151940 Hom.: 36831 Cov.: 31

Gnomad AFR AF: 0.520

Gnomad AMI AF: 0.547

Gnomad AMR AF: 0.778

Gnomad ASJ AF: 0.718

Gnomad EAS AF: 0.991

Gnomad SAS AF: 0.838

Gnomad FIN AF: 0.739

Gnomad MID AF: 0.750

Gnomad NFE AF: 0.724

Gnomad OTH AF: 0.714

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

GnomAD4 genome AF: 0.686 AC: 104380 AN: 152058 Hom.: 36853 Cov.: 31 AF XY: 0.694 AC XY: 51578 AN XY: 74336

African (AFR) AF: 0.519 AC: 21524 AN: 41438

American (AMR) AF: 0.779 AC: 11902 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.718 AC: 2486 AN: 3464

East Asian (EAS) AF: 0.991 AC: 5130 AN: 5176

South Asian (SAS) AF: 0.838 AC: 4034 AN: 4816

European-Finnish (FIN) AF: 0.739 AC: 7814 AN: 10572

Middle Eastern (MID) AF: 0.738 AC: 217 AN: 294

European-Non Finnish (NFE) AF: 0.724 AC: 49260 AN: 67992

Other (OTH) AF: 0.717 AC: 1515 AN: 2112

Alfa AF: 0.720 Hom.: 65642

Bravo AF: 0.682

Asia WGS AF: 0.892 AC: 3100 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.2
DANN	Benign	0.67
PhyloP100		-0.66
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: rs260964; hg19: chr1-39557772; COSMIC: COSV58365621;