22-49883837-G-C

Variant names:

• chr22-49883837-G-C
• rs113598286
• NM_014838.3:c.175G>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_014838.3(ZBED4):​c.175G>C​(p.Ala59Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0003 in 1,611,416 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A59T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0012 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (2 hom.)
• Consequence: ZBED4 NM_014838.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.21
• Publications: 2 publications found

Genes affected

ZBED4 (HGNC:20721): (zinc finger BED-type containing 4) Enables identical protein binding activity. Predicted to be involved in positive regulation of transcription by RNA polymerase II. Located in cytoplasm and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ALG12 (HGNC:19358): (ALG12 alpha-1,6-mannosyltransferase) This gene encodes a member of the glycosyltransferase 22 family. The encoded protein catalyzes the addition of the eighth mannose residue in an alpha-1,6 linkage onto the dolichol-PP-oligosaccharide precursor (dolichol-PP-Man(7)GlcNAc(2)) required for protein glycosylation. Mutations in this gene have been associated with congenital disorder of glycosylation type Ig (CDG-Ig)characterized by abnormal N-glycosylation. [provided by RefSeq, Jul 2008]

ALG12 Gene-Disease associations (from GenCC):

• ALG12-congenital disorder of glycosylation

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003956318).
• BS2: High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZBED4	NM_014838.3	c.175G>C	p.Ala59Pro	missense_variant	Exon 2 of 2	ENST00000216268.6	NP_055653.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZBED4	ENST00000216268.6	c.175G>C	p.Ala59Pro	missense_variant	Exon 2 of 2	1	NM_014838.3	ENSP00000216268.4
ZBED4	ENST00000850559.1	c.175G>C	p.Ala59Pro	missense_variant	Exon 2 of 2			ENSP00000520851.1
ZBED4	ENST00000850560.1	n.260+359G>C		intron_variant	Intron 2 of 3

Frequencies

GnomAD3 genomes AF: 0.00113 AC: 172 AN: 152180 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00391

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000959

GnomAD2 exomes AF: 0.000307 AC: 77 AN: 251088 AF XY: 0.000243

Gnomad AFR exome AF: 0.00388

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000210 AC: 307 AN: 1459118 Hom.: 2 Cov.: 29 AF XY: 0.000192 AC XY: 139 AN XY: 725306

African (AFR) AF: 0.00527 AC: 176 AN: 33406

American (AMR) AF: 0.000224 AC: 10 AN: 44584

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39612

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53388

Middle Eastern (MID) AF: 0.000695 AC: 4 AN: 5752

European-Non Finnish (NFE) AF: 0.0000360 AC: 40 AN: 1109748

Other (OTH) AF: 0.00116 AC: 70 AN: 60294

GnomAD4 genome AF: 0.00116 AC: 177 AN: 152298 Hom.: 2 Cov.: 32 AF XY: 0.00124 AC XY: 92 AN XY: 74480

African (AFR) AF: 0.00402 AC: 167 AN: 41582

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4818

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68022

Other (OTH) AF: 0.000949 AC: 2 AN: 2108

Alfa AF: 0.000245 Hom.: 0

Bravo AF: 0.00131

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000420 AC: 51

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	2.8
DANN	Benign	0.94
DEOGEN2	Benign	0.040	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
PhyloP100		1.2
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.046
Sift	Benign	0.14	T
Sift4G	Benign	0.14	T
Polyphen		0.0	B
Vest4		0.059
MVP		0.068
MPC		0.61
ClinPred		0.0032	T
GERP RS		0.78
Varity_R		0.051
gMVP		0.15
Mutation Taster		=87/13	polymorphism

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: rs113598286; hg19: chr22-50277485;