rs4987174

Variant names:

• chr6-42963477-C-T
• rs4987174
• NM_018960.6:c.716+28C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_018960.6(GNMT):​c.716+28C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0627 in 1,613,276 control chromosomes in the GnomAD database, including 4,369 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.099 (1205 hom., cov: 31)
  • Exomes 𝑓: 0.059 (3164 hom.)
• Consequence: GNMT NM_018960.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.80
• Publications: 6 publications found

Genes affected

GNMT (HGNC:4415): (glycine N-methyltransferase) The protein encoded by this gene is an enzyme that catalyzes the conversion of S-adenosyl-L-methionine (along with glycine) to S-adenosyl-L-homocysteine and sarcosine. This protein is found in the cytoplasm and acts as a homotetramer. Defects in this gene are a cause of GNMT deficiency (hypermethioninemia). Alternative splicing results in multiple transcript variants. Naturally occurring readthrough transcription occurs between the upstream CNPY3 (canopy FGF signaling regulator 3) gene and this gene and is represented with GeneID:107080644. [provided by RefSeq, Jan 2016]

PEX6 (HGNC:8859): (peroxisomal biogenesis factor 6) This gene encodes a member of the AAA (ATPases associated with diverse cellular activities) family of ATPases. This member is a predominantly cytoplasmic protein, which plays a direct role in peroxisomal protein import and is required for PTS1 (peroxisomal targeting signal 1, a C-terminal tripeptide of the sequence ser-lys-leu) receptor activity. Mutations in this gene cause peroxisome biogenesis disorders of complementation group 4 and complementation group 6. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

PEX6 Gene-Disease associations (from GenCC):

• peroxisome biogenesis disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• peroxisome biogenesis disorder 4A (Zellweger)

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Myriad Women’s Health
• peroxisome biogenesis disorder 4B

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• Heimler syndrome 2

  Inheritance: AR Classification: MODERATE Submitted by: G2P
• autosomal recessive cerebellar ataxia-blindness-deafness syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Zellweger spectrum disorders

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CNPY3-GNMT (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 6-42963477-C-T is Benign according to our data. Variant chr6-42963477-C-T is described in ClinVar as Benign. ClinVar VariationId is 1288001.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.216 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018960.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNMT	NM_018960.6	MANE Select	c.716+28C>T		intron	N/A	NP_061833.1
	GNMT	NM_001318865.2		c.659+28C>T		intron	N/A	NP_001305794.1
	CNPY3-GNMT	NM_001318857.2		c.533+28C>T		intron	N/A	NP_001305786.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNMT	ENST00000372808.4	TSL:1 MANE Select	c.716+28C>T		intron	N/A	ENSP00000361894.3
	PEX6	ENST00000970120.1		c.*41+817G>A		intron	N/A	ENSP00000640179.1
	PEX6	ENST00000858651.1		c.*41+817G>A		intron	N/A	ENSP00000528710.1

Frequencies

GnomAD3 genomes AF: 0.0986 AC: 14965 AN: 151828 Hom.: 1200 Cov.: 31

Gnomad AFR AF: 0.219

Gnomad AMI AF: 0.0419

Gnomad AMR AF: 0.0583

Gnomad ASJ AF: 0.0467

Gnomad EAS AF: 0.0556

Gnomad SAS AF: 0.0600

Gnomad FIN AF: 0.0345

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0540

Gnomad OTH AF: 0.0882

GnomAD2 exomes AF: 0.0625 AC: 15712 AN: 251310 AF XY: 0.0603

Gnomad AFR exome AF: 0.216

Gnomad AMR exome AF: 0.0413

Gnomad ASJ exome AF: 0.0457

Gnomad EAS exome AF: 0.0671

Gnomad FIN exome AF: 0.0314

Gnomad NFE exome AF: 0.0543

Gnomad OTH exome AF: 0.0590

GnomAD4 exome AF: 0.0590 AC: 86157 AN: 1461332 Hom.: 3164 Cov.: 40 AF XY: 0.0586 AC XY: 42586 AN XY: 726986

African (AFR) AF: 0.218 AC: 7293 AN: 33464

American (AMR) AF: 0.0437 AC: 1955 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0450 AC: 1175 AN: 26122

East Asian (EAS) AF: 0.0642 AC: 2547 AN: 39698

South Asian (SAS) AF: 0.0615 AC: 5304 AN: 86224

European-Finnish (FIN) AF: 0.0351 AC: 1873 AN: 53398

Middle Eastern (MID) AF: 0.0900 AC: 519 AN: 5766

European-Non Finnish (NFE) AF: 0.0553 AC: 61441 AN: 1111582

Other (OTH) AF: 0.0671 AC: 4050 AN: 60374

GnomAD4 genome AF: 0.0987 AC: 14999 AN: 151944 Hom.: 1205 Cov.: 31 AF XY: 0.0954 AC XY: 7084 AN XY: 74278

African (AFR) AF: 0.220 AC: 9097 AN: 41402

American (AMR) AF: 0.0582 AC: 889 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0467 AC: 162 AN: 3466

East Asian (EAS) AF: 0.0556 AC: 287 AN: 5164

South Asian (SAS) AF: 0.0592 AC: 285 AN: 4812

European-Finnish (FIN) AF: 0.0345 AC: 366 AN: 10602

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0540 AC: 3670 AN: 67918

Other (OTH) AF: 0.0878 AC: 185 AN: 2108

Alfa AF: 0.0716 Hom.: 133

Bravo AF: 0.107

Asia WGS AF: 0.0640 AC: 223 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.14
DANN	Benign	0.50
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4987174; hg19: chr6-42931215; COSMIC: COSV107302317; COSMIC: COSV107302317;