rs11711953

chr3-47998793-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001385682.1(MAP4):c.68G>A(p.Arg23Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0662 in 1,613,960 control chromosomes in the GnomAD database, including 4,031 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R23W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.047 (222 hom., cov: 32)
  • Exomes 𝑓: 0.068 (3809 hom.)
• Consequence: MAP4 NM_001385682.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.53

Genes affected

MAP4 (HGNC:6862): (microtubule associated protein 4) The protein encoded by this gene is a major non-neuronal microtubule-associated protein. This protein contains a domain similar to the microtubule-binding domains of neuronal microtubule-associated protein (MAP2) and microtubule-associated protein tau (MAPT/TAU). This protein promotes microtubule assembly, and has been shown to counteract destabilization of interphase microtubule catastrophe promotion. Cyclin B was found to interact with this protein, which targets cell division cycle 2 (CDC2) kinase to microtubules. The phosphorylation of this protein affects microtubule properties and cell cycle progression. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023638904).
• BP6: Variant 3-47998793-C-T is Benign according to our data. Variant chr3-47998793-C-T is described in ClinVar as [Benign]. Clinvar id is 3056736.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0717 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP4	NM_001385682.1	c.68G>A	p.Arg23Gln	missense_variant	2/21	ENST00000683076.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP4	ENST00000683076.1	c.68G>A	p.Arg23Gln	missense_variant	2/21		NM_001385682.1	A2

Frequencies

GnomAD3 genomes AF: 0.0468 AC: 7124 AN: 152164 Hom.: 222 Cov.: 32

Gnomad AFR AF: 0.0141

Gnomad AMI AF: 0.0473

Gnomad AMR AF: 0.0338

Gnomad ASJ AF: 0.0504

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.0499

Gnomad FIN AF: 0.0416

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0734

Gnomad OTH AF: 0.0478

GnomAD3 exomes AF: 0.0526 AC: 13217 AN: 251290 Hom.: 470 AF XY: 0.0553 AC XY: 7514 AN XY: 135808

Gnomad AFR exome AF: 0.0111

Gnomad AMR exome AF: 0.0233

Gnomad ASJ exome AF: 0.0556

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0496

Gnomad FIN exome AF: 0.0415

Gnomad NFE exome AF: 0.0781

Gnomad OTH exome AF: 0.0623

GnomAD4 exome AF: 0.0682 AC: 99679 AN: 1461678 Hom.: 3809 Cov.: 32 AF XY: 0.0683 AC XY: 49638 AN XY: 727134

Gnomad4 AFR exome AF: 0.0100

Gnomad4 AMR exome AF: 0.0260

Gnomad4 ASJ exome AF: 0.0542

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0492

Gnomad4 FIN exome AF: 0.0459

Gnomad4 NFE exome AF: 0.0773

Gnomad4 OTH exome AF: 0.0599

GnomAD4 genome AF: 0.0468 AC: 7122 AN: 152282 Hom.: 222 Cov.: 32 AF XY: 0.0442 AC XY: 3293 AN XY: 74474

Gnomad4 AFR AF: 0.0141

Gnomad4 AMR AF: 0.0337

Gnomad4 ASJ AF: 0.0504

Gnomad4 EAS AF: 0.000965

Gnomad4 SAS AF: 0.0504

Gnomad4 FIN AF: 0.0416

Gnomad4 NFE AF: 0.0734

Gnomad4 OTH AF: 0.0468

Alfa AF: 0.0685 Hom.: 798

Bravo AF: 0.0443

TwinsUK AF: 0.0831 AC: 308

ALSPAC AF: 0.0675 AC: 260

ESP6500AA AF: 0.0168 AC: 74

ESP6500EA AF: 0.0781 AC: 672

ExAC AF: 0.0546 AC: 6635

Asia WGS AF: 0.0200 AC: 72 AN: 3478

EpiCase AF: 0.0764

EpiControl AF: 0.0776

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

MAP4-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 04, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.42
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;.;D;D
MetaRNN	Benign	0.0024	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;.;M;.;.;M;M;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-2.1	N;N;N;.;.;D;D;.
REVEL	Benign	0.11
Sift	Benign	0.037	D;D;D;.;.;T;T;.
Sift4G	Benign	0.39	T;D;T;.;.;D;D;D
Polyphen		1.0	D;.;D;.;.;.;.;.
Vest4		0.29
MPC		0.53
ClinPred		0.027	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.033

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: rs11711953; hg19: chr3-48040283; COSMIC: COSV64245168;