1-25753563-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020379.4(MAN1C1):c.914T>C(p.Val305Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V305M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MAN1C1 NM_020379.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.53

Genes affected

MAN1C1 (HGNC:19080): (mannosidase alpha class 1C member 1) Predicted to enable mannosyl-oligosaccharide 1,2-alpha-mannosidase activity. Predicted to be involved in N-glycan processing. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4052379).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAN1C1	NM_020379.4	c.914T>C	p.Val305Ala	missense_variant	5/12	ENST00000374332.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAN1C1	ENST00000374332.9	c.914T>C	p.Val305Ala	missense_variant	5/12	1	NM_020379.4	P1
MAN1C1	ENST00000263979.7	c.374T>C	p.Val125Ala	missense_variant	6/13	5
MAN1C1	ENST00000374329.1	c.227T>C	p.Val76Ala	missense_variant	4/11	2
MAN1C1	ENST00000473891.1	n.312T>C		non_coding_transcript_exon_variant	4/5	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461232 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726918

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

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 18, 2023

The c.914T>C (p.V305A) alteration is located in exon 5 (coding exon 5) of the MAN1C1 gene. This alteration results from a T to C substitution at nucleotide position 914, causing the valine (V) at amino acid position 305 to be replaced by an alanine (A). 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	0.32
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	21
Dann	Uncertain	0.99
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.41	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.42	T
Sift4G	Benign	0.44	T;D;T;T
Polyphen		0.37	.;B;.;.
Vest4		0.52
MutPred		0.46		.;Gain of disorder (P = 0.0665);.;.;
MVP		0.85
MPC		0.64
ClinPred		0.84	D
GERP RS		3.6
Varity_R		0.16
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-26080054;