chr6-22570140-A-C

Position:

• chr6-22570140-A-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_138574.4(HDGFL1):​c.565A>C​(p.Thr189Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HDGFL1 NM_138574.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.486

Genes affected

HDGFL1 (HGNC:21095): (HDGF like 1) Predicted to enable double-stranded DNA binding activity and transcription coregulator activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

CASC15 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06521079).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HDGFL1	NM_138574.4	c.565A>C	p.Thr189Pro	missense_variant	1/1	ENST00000510882.4	NP_612641.2
LOC105374971	XR_001744025.1	n.489-3979A>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HDGFL1	ENST00000510882.4	c.565A>C	p.Thr189Pro	missense_variant	1/1	6	NM_138574.4	ENSP00000442129.1
CASC15	ENST00000652081.1	n.146-3979A>C		intron_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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

Jun 11, 2021

The c.565A>C (p.T189P) alteration is located in exon 1 (coding exon 1) of the HDGFL1 gene. This alteration results from a A to C substitution at nucleotide position 565, causing the threonine (T) at amino acid position 189 to be replaced by a proline (P). 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	Benign	0.066
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	12
DANN	Benign	0.45
DEOGEN2	Benign	0.0024	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.17	T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.065	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.34	N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.45	N
REVEL	Benign	0.0090
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.19	T
Polyphen		0.0	B
Vest4		0.096
MutPred		0.27		Loss of phosphorylation at T189 (P = 0.0259);
MVP		0.030
MPC		0.67
ClinPred		0.051	T
GERP RS		0.061
Varity_R		0.062
gMVP		0.22

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-22570369;