14-103732671-C-A

Variant names:

• chr14-103732671-C-A
• rs199983149
• NM_024071.4:c.578C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024071.4(ZFYVE21):​c.578C>A​(p.Thr193Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. T193M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ZFYVE21 NM_024071.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.950
• Publications: 0 publications found

Genes affected

ZFYVE21 (HGNC:20760): (zinc finger FYVE-type containing 21) Predicted to enable metal ion binding activity. Predicted to be located in endosome and focal adhesion. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.054597646).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024071.4. 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
	ZFYVE21	NM_024071.4	MANE Select	c.578C>A	p.Thr193Lys	missense	Exon 6 of 7	NP_076976.1	Q9BQ24-1
	ZFYVE21	NM_001198953.2		c.632C>A	p.Thr211Lys	missense	Exon 7 of 8	NP_001185882.1	Q9BQ24-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFYVE21	ENST00000311141.7	TSL:1 MANE Select	c.578C>A	p.Thr193Lys	missense	Exon 6 of 7	ENSP00000310543.2	Q9BQ24-1
	ZFYVE21	ENST00000555501.1	TSL:1	n.3680C>A		non_coding_transcript_exon	Exon 5 of 6
	ZFYVE21	ENST00000944811.1		c.791C>A	p.Thr264Lys	missense	Exon 8 of 9	ENSP00000614870.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459602 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726266

African (AFR) AF: 0.00 AC: 0 AN: 33286

American (AMR) AF: 0.00 AC: 0 AN: 43976

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26010

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86054

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111178

Other (OTH) AF: 0.00 AC: 0 AN: 60278

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	11
DANN	Benign	0.91
DEOGEN2	Benign	0.0079	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.95
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.041
Sift	Benign	0.46	T
Sift4G	Benign	0.77	T
Polyphen		0.041	B
Vest4		0.43
MutPred		0.44		Gain of sheet (P = 0.0016)
MVP		0.093
MPC		0.45
ClinPred		0.062	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.025
gMVP		0.33
Mutation Taster		=76/24	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: rs199983149; hg19: chr14-104199008;