X-136224853-T-C

Variant names:

• chrX-136224853-T-C
• rs774025753
• NM_024597.4:c.2167A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_024597.4(MAP7D3):​c.2167A>G​(p.Arg723Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000348 in 1,179,445 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 11 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000037 (0 hom. 11 hem.)
• Consequence: MAP7D3 NM_024597.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.528
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24440101).
• BS2: High Hemizygotes in GnomAdExome4 at 11 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024597.4. 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
	MAP7D3	NM_024597.4	MANE Select	c.2167A>G	p.Arg723Gly	missense	Exon 14 of 19	NP_078873.2
	MAP7D3	NM_001173516.1		c.2113A>G	p.Arg705Gly	missense	Exon 14 of 19	NP_001166987.1	Q8IWC1-4
	MAP7D3	NM_001173517.2		c.2062A>G	p.Arg688Gly	missense	Exon 13 of 18	NP_001166988.1	Q8IWC1-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP7D3	ENST00000316077.14	TSL:1 MANE Select	c.2167A>G	p.Arg723Gly	missense	Exon 14 of 19	ENSP00000318086.9	Q8IWC1-1
	MAP7D3	ENST00000370661.5	TSL:1	c.2062A>G	p.Arg688Gly	missense	Exon 13 of 18	ENSP00000359695.1	Q8IWC1-3
	MAP7D3	ENST00000370660.3	TSL:1	c.2044A>G	p.Arg682Gly	missense	Exon 14 of 17	ENSP00000359694.3	A0A0A0MRP0

Frequencies

GnomAD3 genomes AF: 0.00000889 AC: 1 AN: 112494 Hom.: 0 Cov.: 23

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000561 AC: 1 AN: 178288 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000125

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000375 AC: 40 AN: 1066951 Hom.: 0 Cov.: 23 AF XY: 0.0000326 AC XY: 11 AN XY: 337855

African (AFR) AF: 0.0000386 AC: 1 AN: 25917

American (AMR) AF: 0.00 AC: 0 AN: 35098

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19181

East Asian (EAS) AF: 0.00 AC: 0 AN: 30035

South Asian (SAS) AF: 0.00 AC: 0 AN: 53288

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4051

European-Non Finnish (NFE) AF: 0.0000442 AC: 36 AN: 813935

Other (OTH) AF: 0.0000666 AC: 3 AN: 45056

GnomAD4 genome AF: 0.00000889 AC: 1 AN: 112494 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34636

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30998

American (AMR) AF: 0.00 AC: 0 AN: 10644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2654

East Asian (EAS) AF: 0.00 AC: 0 AN: 3600

South Asian (SAS) AF: 0.00 AC: 0 AN: 2687

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6189

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53282

Other (OTH) AF: 0.00 AC: 0 AN: 1517

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000142 Hom.: 1

Bravo AF: 0.0000264

ExAC AF: 0.00000828 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	MAP7D3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	13
DANN	Benign	0.92
DEOGEN2	Benign	0.043	T
FATHMM_MKL	Benign	0.16	N
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		0.53
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Benign	0.22
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.096	T
Polyphen		0.62	P
Vest4		0.60
MutPred		0.59		Loss of stability (P = 0.0194)
MVP		0.38
MPC		0.35
ClinPred		0.46	T
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.43
gMVP		0.28
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs774025753; hg19: chrX-135307012;