1-39453562-A-G

Variant names:

• chr1-39453562-A-G
• rs687848
• NM_001394062.1:c.20743-145A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001394062.1(MACF1):​c.20743-145A>G variant causes a intron change. The variant allele was found at a frequency of 0.543 in 675,280 control chromosomes in the GnomAD database, including 102,311 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.56 (24310 hom., cov: 32)
  • Exomes 𝑓: 0.54 (78001 hom.)
• Consequence: MACF1 NM_001394062.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.63
• Publications: 11 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), Orphanet, PanelApp Australia, Ambry Genetics
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 1-39453562-A-G is Benign according to our data. Variant chr1-39453562-A-G is described in ClinVar as Benign. ClinVar VariationId is 1291665.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.596 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MACF1	NM_001394062.1	c.20743-145A>G		intron_variant	Intron 87 of 100	ENST00000564288.6	NP_001380991.1
MACF1	NM_012090.5	c.14566-145A>G		intron_variant	Intron 82 of 92		NP_036222.3
MACF1	NM_001397473.1	c.8821-145A>G		intron_variant	Intron 30 of 40		NP_001384402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MACF1	ENST00000564288.6	c.20743-145A>G		intron_variant	Intron 87 of 100	5	NM_001394062.1	ENSP00000455274.1

Frequencies

GnomAD3 genomes AF: 0.560 AC: 85200 AN: 152010 Hom.: 24285 Cov.: 32

Gnomad AFR AF: 0.603

Gnomad AMI AF: 0.638

Gnomad AMR AF: 0.484

Gnomad ASJ AF: 0.608

Gnomad EAS AF: 0.361

Gnomad SAS AF: 0.347

Gnomad FIN AF: 0.586

Gnomad MID AF: 0.633

Gnomad NFE AF: 0.575

Gnomad OTH AF: 0.562

GnomAD4 exome AF: 0.538 AC: 281358 AN: 523152 Hom.: 78001 AF XY: 0.529 AC XY: 144426 AN XY: 272944

African (AFR) AF: 0.604 AC: 8241 AN: 13642

American (AMR) AF: 0.448 AC: 8539 AN: 19080

Ashkenazi Jewish (ASJ) AF: 0.616 AC: 8677 AN: 14088

East Asian (EAS) AF: 0.320 AC: 9976 AN: 31200

South Asian (SAS) AF: 0.363 AC: 16446 AN: 45300

European-Finnish (FIN) AF: 0.589 AC: 22309 AN: 37874

Middle Eastern (MID) AF: 0.603 AC: 1265 AN: 2098

European-Non Finnish (NFE) AF: 0.574 AC: 190619 AN: 331880

Other (OTH) AF: 0.546 AC: 15286 AN: 27990

GnomAD4 genome AF: 0.561 AC: 85269 AN: 152128 Hom.: 24310 Cov.: 32 AF XY: 0.553 AC XY: 41122 AN XY: 74366

African (AFR) AF: 0.603 AC: 25005 AN: 41492

American (AMR) AF: 0.483 AC: 7378 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.608 AC: 2111 AN: 3470

East Asian (EAS) AF: 0.360 AC: 1865 AN: 5180

South Asian (SAS) AF: 0.347 AC: 1673 AN: 4826

European-Finnish (FIN) AF: 0.586 AC: 6187 AN: 10566

Middle Eastern (MID) AF: 0.639 AC: 188 AN: 294

European-Non Finnish (NFE) AF: 0.575 AC: 39091 AN: 68000

Other (OTH) AF: 0.565 AC: 1192 AN: 2110

Alfa AF: 0.562 Hom.: 80665

Bravo AF: 0.560

Asia WGS AF: 0.405 AC: 1409 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 13, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	13
DANN	Benign	0.58
PhyloP100		3.6
PromoterAI		0.0098	Neutral
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: rs687848; hg19: chr1-39919234;