19-1863082-T-C

Variant summary

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

The NM_031918.4(KLF16):c.416A>G(p.Tyr139Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000554 in 1,262,580 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: KLF16 NM_031918.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.543

Genes affected

KLF16 (HGNC:16857): (KLF transcription factor 16) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to act upstream of or within dopamine receptor signaling pathway. Predicted to be located in nucleus. Predicted to be part of chromatin. [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/exons	MANE	UniProt
KLF16	NM_031918.4	c.416A>G	p.Tyr139Cys	missense_variant	1/2	ENST00000250916.6
KLF16	XM_047439498.1	c.428-8322A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLF16	ENST00000250916.6	c.416A>G	p.Tyr139Cys	missense_variant	1/2	1	NM_031918.4	P1
KLF16	ENST00000617223.1	c.416A>G	p.Tyr139Cys	missense_variant	1/3	1		P1
KLF16	ENST00000541015.5	c.416A>G	p.Tyr139Cys	missense_variant, NMD_transcript_variant	1/3	1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000554 AC: 7 AN: 1262580 Hom.: 0 Cov.: 31 AF XY: 0.00000639 AC XY: 4 AN XY: 625552

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000702

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 21, 2024

The c.416A>G (p.Y139C) alteration is located in exon 1 (coding exon 1) of the KLF16 gene. This alteration results from a A to G substitution at nucleotide position 416, causing the tyrosine (Y) at amino acid position 139 to be replaced by a cysteine (C). 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	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Benign	-0.22
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.066	T;T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.0086	N
M_CAP	Pathogenic	0.83	D
MetaRNN	Uncertain	0.44	T;T
MetaSVM	Uncertain	0.064	D
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	0.99	N
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-3.6	D;.
REVEL	Uncertain	0.32
Sift	Benign	0.15	T;.
Sift4G	Benign	0.19	T;T
Polyphen		1.0	D;D
Vest4		0.21
MutPred		0.30		Gain of methylation at K140 (P = 0.013);Gain of methylation at K140 (P = 0.013);
MVP		1.0
MPC		2.4
ClinPred		0.90	D
GERP RS		0.14
Varity_R		0.24
gMVP		0.44

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

Publications

LitVar

Other links and lift over

dbSNP: rs1367916072; hg19: chr19-1863081;