18-8706488-G-A

Variant names:

• chr18-8706488-G-A
• rs151052217
• NM_001395333.1:c.828G>A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_001395333.1(MTCL1):​c.828G>A​(p.Ala276Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0193 in 1,269,540 control chromosomes in the GnomAD database, including 306 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.015 (35 hom., cov: 33)
  • Exomes 𝑓: 0.020 (271 hom.)
• Consequence: MTCL1 NM_001395333.1 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0320

Genes affected

MTCL1 (HGNC:29121): (microtubule crosslinking factor 1) Enables microtubule binding activity. Predicted to be involved in establishment or maintenance of epithelial cell apical/basal polarity; microtubule bundle formation; and positive regulation of protein targeting to membrane. Located in midbody and spindle pole. [provided by Alliance of Genome Resources, Apr 2022]

GACAT2 (HGNC:50516): (gastric cancer associated transcript 2)

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 18-8706488-G-A is Benign according to our data. Variant chr18-8706488-G-A is described in ClinVar as [Benign]. Clinvar id is 3068677.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.032 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0153 (2320/151974) while in subpopulation SAS AF= 0.029 (140/4822). AF 95% confidence interval is 0.0251. There are 35 homozygotes in gnomad4. There are 1166 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 35 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTCL1	NM_001395333.1	c.828G>A	p.Ala276Ala	synonymous_variant	Exon 1 of 15	ENST00000695636.1	NP_001382262.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTCL1	ENST00000695636.1	c.828G>A	p.Ala276Ala	synonymous_variant	Exon 1 of 15		NM_001395333.1	ENSP00000512073.1
MTCL1	ENST00000695635.1	c.828G>A	p.Ala276Ala	synonymous_variant	Exon 1 of 14			ENSP00000512072.1
MTCL1	ENST00000306329.16	c.828G>A	p.Ala276Ala	synonymous_variant	Exon 1 of 15	5		ENSP00000305027.11
GACAT2	ENST00000579368.2	n.630+582C>T		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes AF: 0.0153 AC: 2319 AN: 151868 Hom.: 34 Cov.: 33

Gnomad AFR AF: 0.00386

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.0129

Gnomad ASJ AF: 0.0597

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0282

Gnomad FIN AF: 0.0142

Gnomad MID AF: 0.0764

Gnomad NFE AF: 0.0197

Gnomad OTH AF: 0.0254

GnomAD3 exomes AF: 0.0275 AC: 15 AN: 546 Hom.: 0 AF XY: 0.0242 AC XY: 8 AN XY: 330

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0431

Gnomad NFE exome AF: 0.0234

Gnomad OTH exome AF: 0.0625

GnomAD4 exome AF: 0.0198 AC: 22129 AN: 1117566 Hom.: 271 Cov.: 36 AF XY: 0.0202 AC XY: 10743 AN XY: 531770

Gnomad4 AFR exome AF: 0.00318

Gnomad4 AMR exome AF: 0.0149

Gnomad4 ASJ exome AF: 0.0545

Gnomad4 EAS exome AF: 0.0000377

Gnomad4 SAS exome AF: 0.0349

Gnomad4 FIN exome AF: 0.0127

Gnomad4 NFE exome AF: 0.0198

Gnomad4 OTH exome AF: 0.0221

GnomAD4 genome AF: 0.0153 AC: 2320 AN: 151974 Hom.: 35 Cov.: 33 AF XY: 0.0157 AC XY: 1166 AN XY: 74312

Gnomad4 AFR AF: 0.00385

Gnomad4 AMR AF: 0.0128

Gnomad4 ASJ AF: 0.0597

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0290

Gnomad4 FIN AF: 0.0142

Gnomad4 NFE AF: 0.0197

Gnomad4 OTH AF: 0.0247

Alfa AF: 0.0148 Hom.: 1

Bravo AF: 0.0151

Asia WGS AF: 0.0100 AC: 36 AN: 3462

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cerebellar ataxia Benign:1

May 04, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

European Non-Finnish population allele frequency is 1.223% (rs151052217, 239/15674 alleles, 1 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, this variant is classified as BENIGN. Following criteria are met: BA1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	4.8
DANN	Benign	0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs151052217; hg19: chr18-8706486;