1-25749257-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_020379.4(MAN1C1):c.756C>T(p.Ser252=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00184 in 1,611,306 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0093 (21 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (21 hom.)
• Consequence: MAN1C1 NM_020379.4 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.61

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 1-25749257-C-T is Benign according to our data. Variant chr1-25749257-C-T is described in ClinVar as [Benign]. Clinvar id is 783280.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.61 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00928 (1414/152300) while in subpopulation AFR AF= 0.0315 (1310/41560). AF 95% confidence interval is 0.0301. There are 21 homozygotes in gnomad4. There are 678 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAN1C1	NM_020379.4	c.756C>T	p.Ser252=	splice_region_variant, synonymous_variant	4/12	ENST00000374332.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAN1C1	ENST00000374332.9	c.756C>T	p.Ser252=	splice_region_variant, synonymous_variant	4/12	1	NM_020379.4	P1
MAN1C1	ENST00000263979.7	c.216C>T	p.Ser72=	splice_region_variant, synonymous_variant	5/13	5
MAN1C1	ENST00000374329.1	c.69C>T	p.Ser23=	splice_region_variant, synonymous_variant	3/11	2
MAN1C1	ENST00000473891.1	n.154C>T		splice_region_variant, non_coding_transcript_exon_variant	3/5	4

Frequencies

GnomAD3 genomes AF: 0.00926 AC: 1409 AN: 152182 Hom.: 21 Cov.: 33

Gnomad AFR AF: 0.0315

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00236 AC: 585 AN: 247386 Hom.: 10 AF XY: 0.00181 AC XY: 242 AN XY: 133464

Gnomad AFR exome AF: 0.0296

Gnomad AMR exome AF: 0.00201

Gnomad ASJ exome AF: 0.000910

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.000101

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000232

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00106 AC: 1551 AN: 1459006 Hom.: 21 Cov.: 30 AF XY: 0.000947 AC XY: 687 AN XY: 725432

Gnomad4 AFR exome AF: 0.0315

Gnomad4 AMR exome AF: 0.00206

Gnomad4 ASJ exome AF: 0.000692

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000141

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000196

Gnomad4 OTH exome AF: 0.00234

GnomAD4 genome AF: 0.00928 AC: 1414 AN: 152300 Hom.: 21 Cov.: 33 AF XY: 0.00910 AC XY: 678 AN XY: 74470

Gnomad4 AFR AF: 0.0315

Gnomad4 AMR AF: 0.00359

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00336 Hom.: 4

Bravo AF: 0.0101

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MAN1C1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 28, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 03, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	0.048
Dann	Benign	0.90

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: rs116009723; hg19: chr1-26075748; COSMIC: COSV56042727;