3-196207421-C-T

Variant names:

• chr3-196207421-C-T
• rs868089256
• NM_001039617.2:c.664G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001039617.2(ZDHHC19):​c.664G>A​(p.Ala222Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,416,060 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ZDHHC19 NM_001039617.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.22

Genes affected

ZDHHC19 (HGNC:20713): (zinc finger DHHC-type palmitoyltransferase 19) Enables protein-cysteine S-palmitoyltransferase activity. Involved in peptidyl-L-cysteine S-palmitoylation. Located in Golgi membrane; endoplasmic reticulum; and perinucleolar compartment. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZDHHC19	NM_001039617.2	c.664G>A	p.Ala222Thr	missense_variant	Exon 5 of 8	ENST00000296326.8	NP_001034706.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZDHHC19	ENST00000296326.8	c.664G>A	p.Ala222Thr	missense_variant	Exon 5 of 8	5	NM_001039617.2	ENSP00000296326.3
ZDHHC19	ENST00000397544.6	n.664G>A		non_coding_transcript_exon_variant	Exon 5 of 8	1		ENSP00000380678.2
ZDHHC19	ENST00000465519.5	n.1259G>A		non_coding_transcript_exon_variant	Exon 5 of 8	1
ZDHHC19	ENST00000438232.5	n.664G>A		non_coding_transcript_exon_variant	Exon 5 of 9	2		ENSP00000393710.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1416060 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 700326

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000125

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000171

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 24, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.664G>A (p.A222T) alteration is located in exon 5 (coding exon 5) of the ZDHHC19 gene. This alteration results from a G to A substitution at nucleotide position 664, causing the alanine (A) at amino acid position 222 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.0015	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-0.54	T
MutationAssessor	Pathogenic	2.9	M
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.51	N
REVEL	Benign	0.24
Sift	Benign	0.23	T
Sift4G	Benign	0.14	T
Polyphen		1.0	D
Vest4		0.52
MutPred		0.40		Gain of helix (P = 0.0078);
MVP		0.29
MPC		0.95
ClinPred		0.98	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.15
gMVP		0.38

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

Publications

LitVar

Other links and lift over

dbSNP: rs868089256; hg19: chr3-195934292;