Genetic Variant MAP7D3:p.Arg623Gln (chrX-136228641-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_024597.4(MAP7D3):c.1868G>A(p.Arg623Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000813 in 1,205,706 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 39 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R623L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000071 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.000082 ( 0 hom. 37 hem. )

Consequence

MAP7D3
NM_024597.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.170

Variant links:

Genes affected

MAP7D3 (HGNC:25742): (MAP7 domain containing 3) The protein encoded by this gene belongs to the MAP7 (microtubule-associated protein 7) family. Alternatively spliced transcript variants encoding different isoforms have been found. [provided by RefSeq, Mar 2010]

MAP7D3 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.026488692).

BP6

Variant X-136228641-C-T is Benign according to our data. Variant chrX-136228641-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3870401.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP7D3	NM_024597.4 link	c.1868G>A	p.Arg623Gln	missense_variant	Exon 11 of 19	ENST00000316077.14	NP_078873.2	Q8IWC1-1
MAP7D3	NM_001173516.1 link	c.1814G>A	p.Arg605Gln	missense_variant	Exon 11 of 19		NP_001166987.1	Q8IWC1-4
MAP7D3	NM_001173517.2 link	c.1763G>A	p.Arg588Gln	missense_variant	Exon 10 of 18		NP_001166988.1	Q8IWC1-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP7D3	ENST00000316077.14 link	c.1868G>A	p.Arg623Gln	missense_variant	Exon 11 of 19	1	NM_024597.4	ENSP00000318086.9		Q8IWC1-1

Frequencies

GnomAD3 genomes

AF:

0.0000714

AC:

AN:

112092

Hom.:

Cov.:

AF XY:

0.0000584

AC XY:

AN XY:

34248

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000150

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000579

AC:

AN:

172842

Hom.:

AF XY:

0.0000841

AC XY:

AN XY:

59464

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000127

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000823

AC:

AN:

1093614

Hom.:

Cov.:

AF XY:

0.000103

AC XY:

AN XY:

359534

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000100

Gnomad4 OTH exome

AF:

0.000131

GnomAD4 genome

AF:

0.0000714

AC:

AN:

112092

Hom.:

Cov.:

AF XY:

0.0000584

AC XY:

AN XY:

34248

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000150

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000217

Hom.:

Bravo

AF:

0.0000642

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000346

AC:

ExAC

AF:

0.0000579

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Jan 23, 2025

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.062

DANN

Benign

0.54

DEOGEN2

Benign

0.0018

.;T;.;T

FATHMM_MKL

Benign

0.00063

LIST_S2

Benign

0.57

T;T;T;T

M_CAP

Benign

0.0055

MetaRNN

Benign

0.026

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.1

.;N;.;.

PrimateAI

Benign

0.20

PROVEAN

Benign

1.3

N;N;N;N

REVEL

Benign

0.015

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

1.0

T;T;T;.

Polyphen

0.11

B;B;.;.

Vest4

0.16

MVP

0.28

MPC

0.089

ClinPred

0.022

GERP RS

-2.3

Varity_R

0.027

gMVP

0.0077

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over