ENST00000567887.5:c.83G>C

Variant names:

• chr1-39084301-G-C
• rs775020443
• ENST00000567887.5:c.83G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000567887.5(MACF1):​c.83G>C​(p.Ser28Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S28S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MACF1 ENST00000567887.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.05

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25224686).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MACF1	NM_012090.5	c.83G>C	p.Ser28Thr	missense_variant	Exon 1 of 93		NP_036222.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MACF1	ENST00000567887.5	c.83G>C	p.Ser28Thr	missense_variant	Exon 1 of 101	5		ENSP00000455823.1
MACF1	ENST00000372915.8	c.83G>C	p.Ser28Thr	missense_variant	Exon 1 of 96	5		ENSP00000362006.4
MACF1	ENST00000361689.7	c.83G>C	p.Ser28Thr	missense_variant	Exon 2 of 94	5		ENSP00000354573.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

May 19, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	0.00039	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T;T;T;T;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.72	.;T;T;T;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.25	T;T;T;T;T
MetaSVM	Benign	-0.52	T
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.5	N;.;N;N;N
REVEL	Benign	0.18
Sift	Pathogenic	0.0	D;.;D;D;D
Sift4G	Uncertain	0.035	D;D;.;.;D
Vest4		0.35
MutPred		0.078		Gain of MoRF binding (P = 0.1265);Gain of MoRF binding (P = 0.1265);Gain of MoRF binding (P = 0.1265);Gain of MoRF binding (P = 0.1265);Gain of MoRF binding (P = 0.1265);
MVP		0.63
ClinPred		0.91	D
GERP RS		5.3
Varity_R		0.35
gMVP		0.44

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

Publications

LitVar

Other links and lift over

dbSNP: rs775020443; hg19: chr1-39549973;