4-373410-A-T

Variant names:

• chr4-373410-A-T
• rs114931928
• NM_003441.4:c.973A>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PM2 BP4_Strong BP6_Very_Strong

The NM_003441.4(ZNF141):​c.973A>T​(p.Thr325Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T325T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZNF141 NM_003441.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.191
• Publications: 12 publications found

Genes affected

ZNF141 (HGNC:12926): (zinc finger protein 141) The protein encoded by this gene is a zinc finger protein that may be a tumor suppressor. Defects in this gene have been associated with autosomal recessive postaxial polydactyly type A. [provided by RefSeq, Jan 2017]

ZNF141 Gene-Disease associations (from GenCC):

• postaxial polydactyly type A

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• polydactyly, postaxial, type A6

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0031918883).
• BP6: Variant 4-373410-A-T is Benign according to our data. Variant chr4-373410-A-T is described in ClinVar as Benign. ClinVar VariationId is 403622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003441.4. 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
	ZNF141	NM_003441.4	MANE Select	c.973A>T	p.Thr325Ser	missense	Exon 4 of 4	NP_003432.1	Q15928
	ZNF141	NM_001348277.2		c.745A>T	p.Thr249Ser	missense	Exon 2 of 2	NP_001335206.1	Q4W5N2
	ZNF141	NM_001348278.2		c.570+403A>T		intron	N/A	NP_001335207.1	D6RIY0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF141	ENST00000240499.8	TSL:1 MANE Select	c.973A>T	p.Thr325Ser	missense	Exon 4 of 4	ENSP00000240499.7	Q15928
	ZNF141	ENST00000512994.5	TSL:1	c.570+403A>T		intron	N/A	ENSP00000425799.1	D6RIY0
	ZNF141	ENST00000885054.1		c.1108A>T	p.Thr370Ser	missense	Exon 5 of 5	ENSP00000555113.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000707 AC: 10 AN: 141426 AF XY: 0.0000780

Gnomad AFR exome AF: 0.0000906

Gnomad AMR exome AF: 0.0000444

Gnomad ASJ exome AF: 0.000228

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000321

Gnomad NFE exome AF: 0.0000647

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461816 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727200

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111988

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

Alfa AF: 0.000827 Hom.: 0

ExAC AF: 0.0702 AC: 8524

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.5
DANN	Benign	0.94
DEOGEN2	Benign	0.048	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.00028	N
LIST_S2	Benign	0.048	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.085	N
PhyloP100		0.19
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.018
Sift	Benign	0.46	T
Sift4G	Benign	0.95	T
Polyphen		0.034	B
Vest4		0.035
MutPred		0.24		Loss of glycosylation at T324 (P = 0.0868)
MPC		0.13
ClinPred		0.0056	T
GERP RS		-0.029
Varity_R		0.069
gMVP		0.010
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: rs114931928; hg19: chr4-367199; COSMIC: COSV53656576; COSMIC: COSV53656576;