rs138819868

Variant names:

• chr1-39485632-T-G
• rs138819868
• NM_001394062.1:c.22506T>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001394062.1(MACF1):​c.22506T>G​(p.Phe7502Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00374 in 1,614,186 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F7502S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (16 hom.)
• Consequence: MACF1 NM_001394062.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.0620
• Publications: 10 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006961316).
• BP6: Variant 1-39485632-T-G is Benign according to our data. Variant chr1-39485632-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 438598.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00282 (429/152310) while in subpopulation NFE AF = 0.00453 (308/68030). AF 95% confidence interval is 0.00411. There are 1 homozygotes in GnomAd4. There are 195 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 429 AD gene.

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.22506T>G	p.Phe7502Leu	missense	Exon 101 of 101	NP_001380991.1	H3BPE1
	MACF1	NM_012090.5		c.16131T>G	p.Phe5377Leu	missense	Exon 93 of 93	NP_036222.3	Q9UPN3-2
	MACF1	NM_001397473.1		c.10386T>G	p.Phe3462Leu	missense	Exon 41 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.22506T>G	p.Phe7502Leu	missense	Exon 101 of 101	ENSP00000455274.1	H3BPE1
	MACF1	ENST00000497807.1	TSL:1	n.1334T>G		non_coding_transcript_exon	Exon 3 of 3
	MACF1	ENST00000567887.5	TSL:5	c.22617T>G	p.Phe7539Leu	missense	Exon 101 of 101	ENSP00000455823.1	H3BQK9

Frequencies

GnomAD3 genomes AF: 0.00282 AC: 429 AN: 152192 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00292

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00453

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00225 AC: 566 AN: 251426 AF XY: 0.00247

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.000983

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00231

Gnomad NFE exome AF: 0.00403

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.00383 AC: 5601 AN: 1461876 Hom.: 16 Cov.: 30 AF XY: 0.00374 AC XY: 2723 AN XY: 727236

African (AFR) AF: 0.000627 AC: 21 AN: 33480

American (AMR) AF: 0.000805 AC: 36 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000383 AC: 10 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86258

European-Finnish (FIN) AF: 0.00247 AC: 132 AN: 53418

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.00466 AC: 5179 AN: 1111998

Other (OTH) AF: 0.00328 AC: 198 AN: 60394

GnomAD4 genome AF: 0.00282 AC: 429 AN: 152310 Hom.: 1 Cov.: 32 AF XY: 0.00262 AC XY: 195 AN XY: 74470

African (AFR) AF: 0.000818 AC: 34 AN: 41564

American (AMR) AF: 0.00131 AC: 20 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00292 AC: 31 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00453 AC: 308 AN: 68030

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00364 Hom.: 6

Bravo AF: 0.00296

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00419 AC: 36

ExAC AF: 0.00245 AC: 298

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00409

EpiControl AF: 0.00427

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	Abnormal corpus callosum morphology (1)
-	-	1	MACF1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Benign	0.046
Eigen_PC	Benign	0.064
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.0070	T
MetaSVM	Benign	-0.74	T
PhyloP100		-0.062
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.2	D
REVEL	Uncertain	0.29
Sift	Benign	0.070	T
Sift4G	Uncertain	0.0020	D
Polyphen		0.89	P
Vest4		0.42
MutPred		0.17		Gain of loop (P = 0.0502)
MVP		0.68
ClinPred		0.063	T
GERP RS		4.5
Varity_R		0.32
gMVP		0.19
Mutation Taster		=92/8	polymorphism

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: rs138819868; hg19: chr1-39951304; COSMIC: COSV106090172;