rs2296173

chr1-39447679-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001394062.1(MACF1):c.19762-13A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.197 in 1,613,926 control chromosomes in the GnomAD database, including 33,080 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2431 hom., cov: 32)
  • Exomes 𝑓: 0.20 (30649 hom.)
• Consequence: MACF1 NM_001394062.1 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.713

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 1-39447679-A-G is Benign according to our data. Variant chr1-39447679-A-G is described in ClinVar as [Benign]. Clinvar id is 1178452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.216 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MACF1	NM_001394062.1	c.19762-13A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000564288.6
MACF1	NM_001397473.1	c.7840-13A>G		splice_polypyrimidine_tract_variant, intron_variant
MACF1	NM_012090.5	c.13585-13A>G		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MACF1	ENST00000564288.6	c.19762-13A>G		splice_polypyrimidine_tract_variant, intron_variant		5	NM_001394062.1

Frequencies

GnomAD3 genomes AF: 0.160 AC: 24367 AN: 152070 Hom.: 2430 Cov.: 32

Gnomad AFR AF: 0.0408

Gnomad AMI AF: 0.0998

Gnomad AMR AF: 0.188

Gnomad ASJ AF: 0.227

Gnomad EAS AF: 0.175

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.205

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.219

Gnomad OTH AF: 0.176

GnomAD3 exomes AF: 0.189 AC: 47344 AN: 250542 Hom.: 4847 AF XY: 0.187 AC XY: 25332 AN XY: 135756

Gnomad AFR exome AF: 0.0380

Gnomad AMR exome AF: 0.220

Gnomad ASJ exome AF: 0.231

Gnomad EAS exome AF: 0.177

Gnomad SAS exome AF: 0.109

Gnomad FIN exome AF: 0.204

Gnomad NFE exome AF: 0.217

Gnomad OTH exome AF: 0.185

GnomAD4 exome AF: 0.200 AC: 292877 AN: 1461738 Hom.: 30649 Cov.: 33 AF XY: 0.198 AC XY: 144125 AN XY: 727182

Gnomad4 AFR exome AF: 0.0342

Gnomad4 AMR exome AF: 0.217

Gnomad4 ASJ exome AF: 0.235

Gnomad4 EAS exome AF: 0.167

Gnomad4 SAS exome AF: 0.113

Gnomad4 FIN exome AF: 0.197

Gnomad4 NFE exome AF: 0.213

Gnomad4 OTH exome AF: 0.185

GnomAD4 genome AF: 0.160 AC: 24364 AN: 152188 Hom.: 2431 Cov.: 32 AF XY: 0.158 AC XY: 11724 AN XY: 74400

Gnomad4 AFR AF: 0.0408

Gnomad4 AMR AF: 0.188

Gnomad4 ASJ AF: 0.227

Gnomad4 EAS AF: 0.175

Gnomad4 SAS AF: 0.107

Gnomad4 FIN AF: 0.205

Gnomad4 NFE AF: 0.219

Gnomad4 OTH AF: 0.175

Alfa AF: 0.207 Hom.: 4780

Bravo AF: 0.156

Asia WGS AF: 0.120 AC: 414 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Lissencephaly 9 with complex brainstem malformation Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	0.074
Dann	Benign	0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2296173; hg19: chr1-39913351; COSMIC: COSV57112389; COSMIC: COSV57112389;