15-43521967-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP2 PP3

The NM_002373.6(MAP1A):c.494A>C(p.His165Pro) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MAP1A NM_002373.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

Genes affected

MAP1A (HGNC:6835): (microtubule associated protein 1A) This gene encodes a protein that belongs to the microtubule-associated protein family. The proteins of this family are thought to be involved in microtubule assembly, which is an essential step in neurogenesis. The product of this gene is a precursor polypeptide that presumably undergoes proteolytic processing to generate the final MAP1A heavy chain and LC2 light chain. Expression of this gene is almost exclusively in the brain. Studies of the rat microtubule-associated protein 1A gene suggested a role in early events of spinal cord development. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PP2: Missense variant where missense usually causes diseases, MAP1A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.755

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP1A	NM_002373.6	c.494A>C	p.His165Pro	missense_variant	4/6	ENST00000300231.6
MAP1A	NM_001411089.1	c.1208A>C	p.His403Pro	missense_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP1A	ENST00000300231.6	c.494A>C	p.His165Pro	missense_variant	4/6	5	NM_002373.6	P2
MAP1A	ENST00000382031.5	c.1208A>C	p.His403Pro	missense_variant	5/7	5		A2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1 AN: 152170 Hom.: 0 Cov.: 32 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000240 AC: 349 AN: 1457106 Hom.: 0 Cov.: 34 AF XY: 0.000228 AC XY: 165 AN XY: 725070

Gnomad4 AFR exome AF: 0.000240

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000929

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000286

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000657 AC: 1 AN: 152288 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74490

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 24, 2022

The c.494A>C (p.H165P) alteration is located in exon 4 (coding exon 1) of the MAP1A gene. This alteration results from a A to C substitution at nucleotide position 494, causing the histidine (H) at amino acid position 165 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
Cadd	Pathogenic	27
Dann	Benign	0.97
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.012	T
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-6.8	D;D
REVEL	Uncertain	0.55
Sift	Uncertain	0.024	D;D
Sift4G	Uncertain	0.015	D;D
Polyphen		1.0	.;D
Vest4		0.78
MutPred		0.43		.;Loss of helix (P = 0.2662);
MVP		0.42
MPC		0.94
ClinPred		0.98	D
GERP RS		5.1
Varity_R		0.81
gMVP		0.98

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: rs2079320981; hg19: chr15-43814165;