rs2296172

Variant names:

• chr1-39370145-A-G
• rs2296172
• NM_001394062.1:c.13054A>G

Your query was ambiguous. Multiple possible variants found:

• chr1-39370145-A-G
• chr1-39370145-A-T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BA1

The NM_001394062.1(MACF1):​c.13054A>G​(p.Met4352Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.196 in 1,613,338 control chromosomes in the GnomAD database, including 33,104 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2441 hom., cov: 32)
  • Exomes 𝑓: 0.20 (30663 hom.)
• Consequence: MACF1 NM_001394062.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.409
• Publications: 73 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 -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 1-39370145-A-G is Benign according to our data. Variant chr1-39370145-A-G is described in ClinVar as Benign. ClinVar VariationId is 1232730.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.

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.13054A>G	p.Met4352Val	missense	Exon 51 of 101	NP_001380991.1
	MACF1	NM_012090.5		c.6868A>G	p.Met2290Val	missense	Exon 45 of 93	NP_036222.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MACF1	ENST00000564288.6	TSL:5 MANE Select	c.13054A>G	p.Met4352Val	missense	Exon 51 of 101	ENSP00000455274.1
	MACF1	ENST00000567887.5	TSL:5	c.13165A>G	p.Met4389Val	missense	Exon 51 of 101	ENSP00000455823.1
	MACF1	ENST00000372915.8	TSL:5	c.13069A>G	p.Met4357Val	missense	Exon 50 of 96	ENSP00000362006.4

Frequencies

GnomAD3 genomes AF: 0.160 AC: 24334 AN: 152104 Hom.: 2441 Cov.: 32

Gnomad AFR AF: 0.0399

Gnomad AMI AF: 0.0998

Gnomad AMR AF: 0.188

Gnomad ASJ AF: 0.227

Gnomad EAS AF: 0.175

Gnomad SAS AF: 0.108

Gnomad FIN AF: 0.205

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.219

Gnomad OTH AF: 0.177

GnomAD2 exomes AF: 0.188 AC: 47236 AN: 250828 AF XY: 0.186

Gnomad AFR exome AF: 0.0375

Gnomad AMR exome AF: 0.219

Gnomad ASJ exome AF: 0.231

Gnomad EAS exome AF: 0.177

Gnomad FIN exome AF: 0.204

Gnomad NFE exome AF: 0.217

Gnomad OTH exome AF: 0.183

GnomAD4 exome AF: 0.200 AC: 292667 AN: 1461116 Hom.: 30663 Cov.: 32 AF XY: 0.198 AC XY: 144039 AN XY: 726846

African (AFR) AF: 0.0331 AC: 1109 AN: 33476

American (AMR) AF: 0.216 AC: 9647 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.235 AC: 6138 AN: 26122

East Asian (EAS) AF: 0.167 AC: 6642 AN: 39666

South Asian (SAS) AF: 0.113 AC: 9719 AN: 86196

European-Finnish (FIN) AF: 0.197 AC: 10502 AN: 53386

Middle Eastern (MID) AF: 0.156 AC: 901 AN: 5768

European-Non Finnish (NFE) AF: 0.213 AC: 236894 AN: 1111470

Other (OTH) AF: 0.184 AC: 11115 AN: 60360

GnomAD4 genome AF: 0.160 AC: 24326 AN: 152222 Hom.: 2441 Cov.: 32 AF XY: 0.157 AC XY: 11690 AN XY: 74422

African (AFR) AF: 0.0398 AC: 1655 AN: 41566

American (AMR) AF: 0.187 AC: 2862 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.227 AC: 788 AN: 3470

East Asian (EAS) AF: 0.175 AC: 907 AN: 5184

South Asian (SAS) AF: 0.108 AC: 521 AN: 4828

European-Finnish (FIN) AF: 0.205 AC: 2165 AN: 10586

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.219 AC: 14903 AN: 67996

Other (OTH) AF: 0.175 AC: 369 AN: 2112

Alfa AF: 0.197 Hom.: 11139

Bravo AF: 0.156

TwinsUK AF: 0.211 AC: 782

ALSPAC AF: 0.206 AC: 793

ESP6500AA AF: 0.0440 AC: 194

ESP6500EA AF: 0.223 AC: 1919

ExAC AF: 0.183 AC: 22265

Asia WGS AF: 0.118 AC: 410 AN: 3478

EpiCase AF: 0.213

EpiControl AF: 0.218

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Lissencephaly 9 with complex brainstem malformation (1)
-	-	1	MACF1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	18
DANN	Benign	0.50
DEOGEN2	Benign	0.063	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-0.97	T
PhyloP100		0.41
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.084
Sift	Benign	0.85	T
Sift4G	Benign	0.24	T
Polyphen		0.0	B
Vest4		0.039
ClinPred		0.0055	T
GERP RS		0.35
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.031
gMVP		0.21
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.63		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.63		Position offset: -1

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

Other links and lift over

dbSNP: rs2296172; hg19: chr1-39835817; COSMIC: COSV57112365;