rs111229124

Variant names:

• chr16-49636012-G-A
• rs111229124
• NM_001379286.1:c.3164C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-49636012-G-A
• chr16-49636012-G-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001379286.1(ZNF423):​c.3164C>T​(p.Ala1055Val) variant causes a missense change. The variant allele was found at a frequency of 0.00852 in 1,606,776 control chromosomes in the GnomAD database, including 81 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1055E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0061 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0088 (75 hom.)
• Consequence: ZNF423 NM_001379286.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 6.62
• Publications: 9 publications found

Genes affected

ZNF423 (HGNC:16762): (zinc finger protein 423) The protein encoded by this gene is a nuclear protein that belongs to the family of Kruppel-like C2H2 zinc finger proteins. It functions as a DNA-binding transcription factor by using distinct zinc fingers in different signaling pathways. Thus, it is thought that this gene may have multiple roles in signal transduction during development. Mutations in this gene are associated with nephronophthisis-14 and Joubert syndrome-19. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2012]

ZNF423 Gene-Disease associations (from GenCC):

• nephronophthisis 14

  Inheritance: Unknown, AD, AR Classification: STRONG, LIMITED Submitted by: Laboratory for Molecular Medicine, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• ciliopathy

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• Joubert syndrome with oculorenal defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• nephronophthisis 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005976796).
• BP6: Variant 16-49636012-G-A is Benign according to our data. Variant chr16-49636012-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260532.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 6 Unknown,AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001379286.1. 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
	ZNF423	NM_001379286.1	MANE Select	c.3164C>T	p.Ala1055Val	missense	Exon 4 of 8	NP_001366215.1	A0A7P0Q1F0
	ZNF423	NM_015069.5		c.3140C>T	p.Ala1047Val	missense	Exon 4 of 8	NP_055884.2
	ZNF423	NM_001271620.2		c.2960C>T	p.Ala987Val	missense	Exon 4 of 8	NP_001258549.1	Q2M1K9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF423	ENST00000563137.7	TSL:5 MANE Select	c.3164C>T	p.Ala1055Val	missense	Exon 4 of 8	ENSP00000455588.3	A0A7P0Q1F0
	ZNF423	ENST00000562520.1	TSL:1	c.2960C>T	p.Ala987Val	missense	Exon 4 of 8	ENSP00000457664.1	Q2M1K9-2
	ZNF423	ENST00000567169.5	TSL:1	c.2789C>T	p.Ala930Val	missense	Exon 2 of 6	ENSP00000455061.1	F5H7S1

Frequencies

GnomAD3 genomes AF: 0.00611 AC: 930 AN: 152186 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00205

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00654

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00264

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0102

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00581 AC: 1437 AN: 247334 AF XY: 0.00558

Gnomad AFR exome AF: 0.00161

Gnomad AMR exome AF: 0.00421

Gnomad ASJ exome AF: 0.000823

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00257

Gnomad NFE exome AF: 0.00985

Gnomad OTH exome AF: 0.00729

GnomAD4 exome AF: 0.00877 AC: 12754 AN: 1454472 Hom.: 75 Cov.: 32 AF XY: 0.00855 AC XY: 6176 AN XY: 722198

African (AFR) AF: 0.00183 AC: 61 AN: 33374

American (AMR) AF: 0.00453 AC: 202 AN: 44546

Ashkenazi Jewish (ASJ) AF: 0.00116 AC: 30 AN: 25838

East Asian (EAS) AF: 0.00 AC: 0 AN: 39534

South Asian (SAS) AF: 0.00189 AC: 162 AN: 85590

European-Finnish (FIN) AF: 0.00316 AC: 167 AN: 52926

Middle Eastern (MID) AF: 0.00192 AC: 11 AN: 5744

European-Non Finnish (NFE) AF: 0.0106 AC: 11702 AN: 1106882

Other (OTH) AF: 0.00698 AC: 419 AN: 60038

GnomAD4 genome AF: 0.00611 AC: 930 AN: 152304 Hom.: 6 Cov.: 33 AF XY: 0.00563 AC XY: 419 AN XY: 74472

African (AFR) AF: 0.00204 AC: 85 AN: 41588

American (AMR) AF: 0.00653 AC: 100 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4826

European-Finnish (FIN) AF: 0.00264 AC: 28 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0102 AC: 695 AN: 68014

Other (OTH) AF: 0.00332 AC: 7 AN: 2110

Alfa AF: 0.00777 Hom.: 5

Bravo AF: 0.00590

TwinsUK AF: 0.00890 AC: 33

ALSPAC AF: 0.0109 AC: 42

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00953 AC: 82

ExAC AF: 0.00583 AC: 708

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Nephronophthisis 14 (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.55
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.087	T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.080
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0060	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.34	N
PhyloP100		6.6
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.044
Sift	Benign	0.038	D
Sift4G	Uncertain	0.012	D
Polyphen		0.0040	B
Vest4		0.13
MVP		0.043
MPC		0.37
ClinPred		0.018	T
GERP RS		5.1
Varity_R		0.13
gMVP		0.22
Mutation Taster		=100/0	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: rs111229124; hg19: chr16-49669923; COSMIC: COSV52203203;