1-235448220-CAAAAAAAAAAAAAA-CAAAAAAAAAAAAAAAAAA

Variant names:

• chr1-235448220-C-CAAAA
• rs59405398
• NM_152490.5:c.*1982_*1985dupTTTT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_152490.5(B3GALNT2):​c.*1982_*1985dupTTTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00479 in 462,840 control chromosomes in the GnomAD database, including 4 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0046 (6 hom., cov: 24)
  • Exomes 𝑓: 0.0048 (4 hom.)
  • Failed GnomAD Quality Control
• Consequence: B3GALNT2 NM_152490.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.40
• Publications: 0 publications found

Genes affected

B3GALNT2 (HGNC:28596): (beta-1,3-N-acetylgalactosaminyltransferase 2) This gene encodes a member of the glycosyltransferase 31 family. The encoded protein synthesizes GalNAc:beta-1,3GlcNAc, a novel carbohydrate structure, on N- and O-glycans. Alternatively spliced transcript variants that encode different isoforms have been described. [provided by RefSeq, Mar 2013]

TBCE (HGNC:11582): (tubulin folding cofactor E) Cofactor E is one of four proteins (cofactors A, D, E, and C) involved in the pathway leading to correctly folded beta-tubulin from folding intermediates. Cofactors A and D are believed to play a role in capturing and stabilizing beta-tubulin intermediates in a quasi-native confirmation. Cofactor E binds to the cofactor D/beta-tubulin complex; interaction with cofactor C then causes the release of beta-tubulin polypeptides that are committed to the native state. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

TBCE Gene-Disease associations (from GenCC):

• hypoparathyroidism-retardation-dysmorphism syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet, G2P
• early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• encephalopathy, progressive, with amyotrophy and optic atrophy

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: PanelApp Australia, ClinGen, G2P, Ambry Genetics
• autosomal recessive Kenny-Caffey syndrome

  Inheritance: AR Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet

ENSG00000285053 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152490.5. 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
	B3GALNT2	NM_152490.5	MANE Select	c.*1982_*1985dupTTTT		3_prime_UTR	Exon 12 of 12	NP_689703.1	Q8NCR0-1
	TBCE	NM_003193.5	MANE Select	c.1400-112_1400-109dupAAAA		intron	N/A	NP_003184.1	Q15813-1
	TBCE	NM_001287801.2		c.1553-112_1553-109dupAAAA		intron	N/A	NP_001274730.1	Q15813-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	B3GALNT2	ENST00000366600.8	TSL:1 MANE Select	c.*1982_*1985dupTTTT		3_prime_UTR	Exon 12 of 12	ENSP00000355559.3	Q8NCR0-1
	TBCE	ENST00000642610.2	MANE Select	c.1400-112_1400-109dupAAAA		intron	N/A	ENSP00000494796.1	Q15813-1
	ENSG00000285053	ENST00000647186.1		c.1400-112_1400-109dupAAAA		intron	N/A	ENSP00000494775.1

Frequencies

GnomAD3 genomes AF: 0.00461 AC: 302 AN: 65514 Hom.: 6 Cov.: 24

Gnomad AFR AF: 0.0112

Gnomad AMI AF: 0.00275

Gnomad AMR AF: 0.00318

Gnomad ASJ AF: 0.00183

Gnomad EAS AF: 0.000601

Gnomad SAS AF: 0.00314

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00725

Gnomad NFE AF: 0.00116

Gnomad OTH AF: 0.00583

GnomAD4 exome AF: 0.00479 AC: 2219 AN: 462840 Hom.: 4 AF XY: 0.00489 AC XY: 1227 AN XY: 250890

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

African (AFR) AF: 0.0247 AC: 273 AN: 11034

American (AMR) AF: 0.00306 AC: 74 AN: 24206

Ashkenazi Jewish (ASJ) AF: 0.00406 AC: 62 AN: 15264

East Asian (EAS) AF: 0.000744 AC: 21 AN: 28216

South Asian (SAS) AF: 0.00713 AC: 372 AN: 52168

European-Finnish (FIN) AF: 0.00190 AC: 56 AN: 29420

Middle Eastern (MID) AF: 0.00237 AC: 7 AN: 2956

European-Non Finnish (NFE) AF: 0.00455 AC: 1251 AN: 274784

Other (OTH) AF: 0.00415 AC: 103 AN: 24792

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00462 AC: 303 AN: 65532 Hom.: 6 Cov.: 24 AF XY: 0.00455 AC XY: 139 AN XY: 30550

African (AFR) AF: 0.0112 AC: 234 AN: 20858

American (AMR) AF: 0.00317 AC: 18 AN: 5672

Ashkenazi Jewish (ASJ) AF: 0.00183 AC: 3 AN: 1636

East Asian (EAS) AF: 0.000601 AC: 1 AN: 1664

South Asian (SAS) AF: 0.00316 AC: 5 AN: 1582

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2484

Middle Eastern (MID) AF: 0.00794 AC: 1 AN: 126

European-Non Finnish (NFE) AF: 0.00116 AC: 35 AN: 30278

Other (OTH) AF: 0.00576 AC: 5 AN: 868

Alfa AF: 0.00261 Hom.: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.4
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs59405398; hg19: chr1-235611535;