1-37794687-G-C

Position:

• chr1-37794687-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000373045.11(MANEAL):​c.505G>C​(p.Glu169Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,454,526 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: MANEAL ENST00000373045.11 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.14

Genes affected

MANEAL (HGNC:26452): (mannosidase endo-alpha like) Predicted to enable alpha-mannosidase activity. Predicted to be located in Golgi membrane. Predicted to be integral component of membrane. Predicted to be active in Golgi apparatus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1081382).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MANEAL	NM_001113482.2	c.505G>C	p.Glu169Gln	missense_variant	1/4	ENST00000373045.11	NP_001106954.1
MANEAL	NM_001031740.3	c.505G>C	p.Glu169Gln	missense_variant	1/4		NP_001026910.1
MANEAL	XM_005270510.4	c.505G>C	p.Glu169Gln	missense_variant	1/3		XP_005270567.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MANEAL	ENST00000373045.11	c.505G>C	p.Glu169Gln	missense_variant	1/4	1	NM_001113482.2	ENSP00000362136.6
MANEAL	ENST00000397631.7	c.505G>C	p.Glu169Gln	missense_variant	1/4	1		ENSP00000380755.3
MANEAL	ENST00000532512.1	c.205G>C	p.Glu69Gln	missense_variant	1/3	4		ENSP00000432567.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1454526 Hom.: 0 Cov.: 32 AF XY: 0.0000111 AC XY: 8 AN XY: 723348

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: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 31

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

Jul 19, 2022

The c.505G>C (p.E169Q) alteration is located in exon 1 (coding exon 1) of the MANEAL gene. This alteration results from a G to C substitution at nucleotide position 505, causing the glutamic acid (E) at amino acid position 169 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	0.090
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.026	T;.;T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.052
FATHMM_MKL	Benign	0.54	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.0	L;L;.
MutationTaster	Benign	0.94	N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.22	N;N;N
REVEL	Benign	0.019
Sift	Benign	0.38	T;T;T
Sift4G	Benign	0.56	T;T;T
Polyphen		0.17	B;B;.
Vest4		0.063
MutPred		0.14		Loss of glycosylation at S165 (P = 0.1634);Loss of glycosylation at S165 (P = 0.1634);.;
MVP		0.20
MPC		1.5
ClinPred		0.33	T
GERP RS		3.7
Varity_R		0.11
gMVP		0.44

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: rs1646629046; hg19: chr1-38260359;