rs762310765

Variant names:

• chr19-58479936-C-A
• rs762310765
• NM_017908.4:c.719C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-58479936-C-A
• chr19-58479936-C-G
• chr19-58479936-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_017908.4(ZNF446):​c.719C>A​(p.Pro240Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000702 in 1,424,340 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. P240L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: ZNF446 NM_017908.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.594
• Publications: 0 publications found

Genes affected

ZNF446 (HGNC:21036): (zinc finger protein 446) Enables identical protein binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Located in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

SLC27A5 (HGNC:10999): (solute carrier family 27 member 5) The protein encoded by this gene is an isozyme of very long-chain acyl-CoA synthetase (VLCS). It is capable of activating very long-chain fatty-acids containing 24- and 26-carbons. It is expressed in liver and associated with endoplasmic reticulum but not with peroxisomes. Its primary role is in fatty acid elongation or complex lipid synthesis rather than in degradation. This gene has a mouse ortholog. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017908.4. 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
	ZNF446	NM_017908.4	MANE Select	c.719C>A	p.Pro240Gln	missense	Exon 6 of 7	NP_060378.1	Q9NWS9-1
	ZNF446	NM_001304453.1		c.719C>A	p.Pro240Gln	missense	Exon 5 of 6	NP_001291382.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF446	ENST00000594369.6	TSL:1 MANE Select	c.719C>A	p.Pro240Gln	missense	Exon 6 of 7	ENSP00000472802.1	Q9NWS9-1
	ZNF446	ENST00000610298.1	TSL:1	c.719C>A	p.Pro240Gln	missense	Exon 6 of 8	ENSP00000478778.1	Q9NWS9-2
	ZNF446	ENST00000864814.1		c.719C>A	p.Pro240Gln	missense	Exon 5 of 6	ENSP00000534873.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.02e-7 AC: 1 AN: 1424340 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 705756

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

African (AFR) AF: 0.00 AC: 0 AN: 32876

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25378

East Asian (EAS) AF: 0.0000263 AC: 1 AN: 38018

South Asian (SAS) AF: 0.00 AC: 0 AN: 81558

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45900

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1096290

Other (OTH) AF: 0.00 AC: 0 AN: 59174

⚠️ 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 Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.055	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.071	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.83	L
PhyloP100		0.59
PrimateAI	Benign	0.38	T
Sift4G	Uncertain	0.022	D
Polyphen		0.67	P
Vest4		0.25
MutPred		0.35		Loss of glycosylation at P240 (P = 0.0169)
MVP		0.25
MPC		0.38
ClinPred		0.82	D
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.078
gMVP		0.23
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.38		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.38		Position offset: 2

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

Other links and lift over

dbSNP: rs762310765; hg19: chr19-58991303;