3-49422351-T-C

Variant names:

• chr3-49422351-T-C
• rs1415657857
• NM_032316.3:c.*2482A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_032316.3(NICN1):​c.*2482A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NICN1 NM_032316.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.50
• Publications: 0 publications found

Genes affected

NICN1 (HGNC:18317): (nicolin 1, tubulin polyglutamylase complex subunit) This protein encoded by this gene localizes to the nucleus and is expressed in numerous tissues including brain, testis, liver, and kidney. This refseq contains genomic sequence in its 3' UTR which is not supported by experimental evidence. Computer predictions indicate that this region of the 3' UTR contains hairpin-forming self-complementary sequence which is possibly excised after transcription. This gene has a pseudogene on chromosome X. [provided by RefSeq, Jul 2008]

AMT (HGNC:473): (aminomethyltransferase) This gene encodes one of four critical components of the glycine cleavage system. Mutations in this gene have been associated with glycine encephalopathy. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

AMT Gene-Disease associations (from GenCC):

• glycine encephalopathy

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)
• glycine encephalopathy 2

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• infantile glycine encephalopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• neonatal glycine encephalopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• atypical glycine encephalopathy

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000283189 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 3-49422351-T-C is Benign according to our data. Variant chr3-49422351-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1941226.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032316.3. 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
	NICN1	NM_032316.3	MANE Select	c.*2482A>G		3_prime_UTR	Exon 6 of 6	NP_115692.1	Q9BSH3-1
	AMT	NM_000481.4	MANE Select	c.90+10A>G		intron	N/A	NP_000472.2
	AMT	NM_001164712.2		c.90+10A>G		intron	N/A	NP_001158184.1	P48728-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NICN1	ENST00000273598.8	TSL:1 MANE Select	c.*2482A>G		3_prime_UTR	Exon 6 of 6	ENSP00000273598.4	Q9BSH3-1
	AMT	ENST00000273588.9	TSL:1 MANE Select	c.90+10A>G		intron	N/A	ENSP00000273588.3	P48728-1
	ENSG00000283189	ENST00000636166.1	TSL:5	c.496-779A>G		intron	N/A	ENSP00000490106.1	A0A1B0GUH1

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 22 AN: 111858 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000211

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000732

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000350

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000125

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1061454 Hom.: 0 Cov.: 38 AF XY: 0.00 AC XY: 0 AN XY: 532926

African (AFR) AF: 0.00 AC: 0 AN: 24058

American (AMR) AF: 0.00 AC: 0 AN: 39418

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18398

East Asian (EAS) AF: 0.00 AC: 0 AN: 25784

South Asian (SAS) AF: 0.00 AC: 0 AN: 79750

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38758

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4412

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 789214

Other (OTH) AF: 0.00 AC: 0 AN: 41662

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000197 AC: 22 AN: 111858 Hom.: 0 Cov.: 31 AF XY: 0.000229 AC XY: 12 AN XY: 52516

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000211 AC: 6 AN: 28430

American (AMR) AF: 0.000732 AC: 7 AN: 9558

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2948

East Asian (EAS) AF: 0.00 AC: 0 AN: 3534

South Asian (SAS) AF: 0.00 AC: 0 AN: 3154

European-Finnish (FIN) AF: 0.000350 AC: 2 AN: 5714

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.000125 AC: 7 AN: 55942

Other (OTH) AF: 0.00 AC: 0 AN: 1552

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0212 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Glycine encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5
PromoterAI		0.068	Neutral

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1415657857; hg19: chr3-49459784;