rs587404

Variant names:

• chr1-39442834-G-A
• rs587404
• NM_001394062.1:c.19225G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-39442834-G-A
• chr1-39442834-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001394062.1(MACF1):​c.19225G>A​(p.Ala6409Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.303 in 1,613,514 control chromosomes in the GnomAD database, including 76,266 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (9597 hom., cov: 32)
  • Exomes 𝑓: 0.30 (66669 hom.)
• Consequence: MACF1 NM_001394062.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.06
• Publications: 55 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015339851).
• BP6: Variant 1-39442834-G-A is Benign according to our data. Variant chr1-39442834-G-A is described in ClinVar as Benign. ClinVar VariationId is 1266499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.466 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.19225G>A	p.Ala6409Thr	missense	Exon 78 of 101	NP_001380991.1	H3BPE1
	MACF1	NM_012090.5		c.13048G>A	p.Ala4350Thr	missense	Exon 73 of 93	NP_036222.3	Q9UPN3-2
	MACF1	NM_001397473.1		c.7303G>A	p.Ala2435Thr	missense	Exon 21 of 41	NP_001384402.1	O94854-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MACF1	ENST00000564288.6	TSL:5 MANE Select	c.19225G>A	p.Ala6409Thr	missense	Exon 78 of 101	ENSP00000455274.1	H3BPE1
	MACF1	ENST00000567887.5	TSL:5	c.19336G>A	p.Ala6446Thr	missense	Exon 78 of 101	ENSP00000455823.1	H3BQK9
	MACF1	ENST00000372915.8	TSL:5	c.18913G>A	p.Ala6305Thr	missense	Exon 76 of 96	ENSP00000362006.4	A0A7P0MQR8

Frequencies

GnomAD3 genomes AF: 0.346 AC: 52490 AN: 151924 Hom.: 9568 Cov.: 32

Gnomad AFR AF: 0.471

Gnomad AMI AF: 0.216

Gnomad AMR AF: 0.309

Gnomad ASJ AF: 0.309

Gnomad EAS AF: 0.359

Gnomad SAS AF: 0.216

Gnomad FIN AF: 0.259

Gnomad MID AF: 0.415

Gnomad NFE AF: 0.302

Gnomad OTH AF: 0.341

GnomAD2 exomes AF: 0.300 AC: 75074 AN: 250478 AF XY: 0.292

Gnomad AFR exome AF: 0.471

Gnomad AMR exome AF: 0.287

Gnomad ASJ exome AF: 0.307

Gnomad EAS exome AF: 0.363

Gnomad FIN exome AF: 0.259

Gnomad NFE exome AF: 0.299

Gnomad OTH exome AF: 0.292

GnomAD4 exome AF: 0.299 AC: 436809 AN: 1461472 Hom.: 66669 Cov.: 36 AF XY: 0.295 AC XY: 214811 AN XY: 727034

African (AFR) AF: 0.478 AC: 16013 AN: 33470

American (AMR) AF: 0.287 AC: 12827 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.309 AC: 8085 AN: 26132

East Asian (EAS) AF: 0.325 AC: 12897 AN: 39696

South Asian (SAS) AF: 0.214 AC: 18429 AN: 86230

European-Finnish (FIN) AF: 0.254 AC: 13589 AN: 53398

Middle Eastern (MID) AF: 0.315 AC: 1817 AN: 5764

European-Non Finnish (NFE) AF: 0.301 AC: 334928 AN: 1111738

Other (OTH) AF: 0.302 AC: 18224 AN: 60372

GnomAD4 genome AF: 0.346 AC: 52565 AN: 152042 Hom.: 9597 Cov.: 32 AF XY: 0.340 AC XY: 25252 AN XY: 74312

African (AFR) AF: 0.472 AC: 19553 AN: 41452

American (AMR) AF: 0.308 AC: 4712 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.309 AC: 1073 AN: 3472

East Asian (EAS) AF: 0.358 AC: 1850 AN: 5170

South Asian (SAS) AF: 0.216 AC: 1042 AN: 4822

European-Finnish (FIN) AF: 0.259 AC: 2736 AN: 10554

Middle Eastern (MID) AF: 0.412 AC: 121 AN: 294

European-Non Finnish (NFE) AF: 0.302 AC: 20552 AN: 67980

Other (OTH) AF: 0.346 AC: 729 AN: 2104

Alfa AF: 0.317 Hom.: 26791

Bravo AF: 0.357

TwinsUK AF: 0.302 AC: 1121

ALSPAC AF: 0.297 AC: 1144

ESP6500AA AF: 0.470 AC: 2069

ESP6500EA AF: 0.307 AC: 2637

ExAC AF: 0.299 AC: 36362

Asia WGS AF: 0.341 AC: 1185 AN: 3478

EpiCase AF: 0.302

EpiControl AF: 0.308

ClinVar

ClinVar submissions

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	0.052
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	17
DANN	Benign	0.91
DEOGEN2	Benign	0.032	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.037
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.086	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.95	T
PhyloP100		1.1
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	1.7	N
REVEL	Benign	0.077
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.033
ClinPred		0.0046	T
GERP RS		5.8
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.019
gMVP		0.063
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: rs587404; hg19: chr1-39908506; COSMIC: COSV57104949; COSMIC: COSV57104949;