chr1-117402284-G-A

Position:

• chr1-117402284-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006699.5(MAN1A2):​c.401G>A​(p.Arg134Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: MAN1A2 NM_006699.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.492

Genes affected

MAN1A2 (HGNC:6822): (mannosidase alpha class 1A member 2) Alpha-mannosidases function at different stages of N-glycan maturation in mammalian cells. See MAN2A1 (MIM 154582) for general information.[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.049996823).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAN1A2	NM_006699.5	c.401G>A	p.Arg134Gln	missense_variant	2/13	ENST00000356554.7
MAN1A2	XM_006710302.4	c.401G>A	p.Arg134Gln	missense_variant	2/14
MAN1A2	XM_011540536.4	c.401G>A	p.Arg134Gln	missense_variant	2/13
MAN1A2	XM_017000115.2	c.401G>A	p.Arg134Gln	missense_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAN1A2	ENST00000356554.7	c.401G>A	p.Arg134Gln	missense_variant	2/13	1	NM_006699.5	P1
MAN1A2	ENST00000482811.1	n.544-12429G>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461482 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727032

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: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

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

Dec 14, 2022

The c.401G>A (p.R134Q) alteration is located in exon 2 (coding exon 2) of the MAN1A2 gene. This alteration results from a G to A substitution at nucleotide position 401, causing the arginine (R) at amino acid position 134 to be replaced by a glutamine (Q). 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	Benign	0.070
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	13
DANN	Benign	0.87
DEOGEN2	Benign	0.049	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.41	N
MutationTaster	Benign	0.91	D
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.30	N
REVEL	Benign	0.13
Sift	Benign	0.82	T
Sift4G	Benign	0.92	T
Polyphen		0.0	B
Vest4		0.15
MutPred		0.34		Loss of MoRF binding (P = 0.0198);
MVP		0.43
MPC		0.73
ClinPred		0.061	T
GERP RS		-0.095
Varity_R		0.025
gMVP		0.11

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: rs1647460637; hg19: chr1-117944906;