Genetic Variant DNAI4:p.Val827Leu (chr1-66822378-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_024763.5(DNAI4):c.2479G>C(p.Val827Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000871 in 1,606,684 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

DNAI4
NM_024763.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.544

Variant links:

Genes affected

DNAI4 (HGNC:26252): (dynein axonemal intermediate chain 4) Predicted to enable dynein heavy chain binding activity and dynein light chain binding activity. Predicted to be involved in axonemal dynein complex assembly and cilium movement. Predicted to act upstream of or within hematopoietic progenitor cell differentiation. Predicted to be located in axoneme; dynein axonemal particle; and motile cilium. Predicted to be part of axonemal dynein complex. [provided by Alliance of Genome Resources, Apr 2022]

DNAI4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.04998043).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAI4	NM_024763.5 link	c.2479G>C	p.Val827Leu	missense_variant	Exon 16 of 17	ENST00000371026.8	NP_079039.4	Q5VTH9-1A0AVI9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DNAI4	ENST00000371026.8 link	c.2479G>C	p.Val827Leu	missense_variant	Exon 16 of 17	1	NM_024763.5	ENSP00000360065.3	Q5VTH9-1
DNAI4	ENST00000464352.6 link	c.1678G>C	p.Val560Leu	missense_variant	Exon 11 of 12	2		ENSP00000433682.1	H0YDI6
DNAI4	ENST00000491297.6 link	n.*2421G>C		non_coding_transcript_exon_variant	Exon 13 of 14	2		ENSP00000435836.1	H0YEH4
DNAI4	ENST00000491297.6 link	n.*2421G>C		3_prime_UTR_variant	Exon 13 of 14	2		ENSP00000435836.1	H0YEH4

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000245

AC:

AN:

245262

Hom.:

AF XY:

0.0000151

AC XY:

AN XY:

132454

show subpopulations

Gnomad AFR exome

AF:

0.000186

Gnomad AMR exome

AF:

0.0000916

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000344

AC:

AN:

1454598

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723330

show subpopulations

Gnomad4 AFR exome

AF:

0.0000302

Gnomad4 AMR exome

AF:

0.0000700

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:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152086

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000680

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 27, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2479G>C (p.V827L) alteration is located in exon 16 (coding exon 16) of the WDR78 gene. This alteration results from a G to C substitution at nucleotide position 2479, causing the valine (V) at amino acid position 827 to be replaced by a leucine (L). 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

0.085

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.67

CADD

Benign

0.86

DANN

Benign

0.79

DEOGEN2

Benign

0.0022

T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.090

LIST_S2

Benign

0.48

T;T

M_CAP

Benign

0.0057

MetaRNN

Benign

0.050

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;.

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.50

N;N

REVEL

Benign

0.015

Sift

Benign

0.21

T;T

Sift4G

Benign

0.35

T;T

Polyphen

0.0040

B;.

Vest4

0.089

MVP

0.12

MPC

0.097

ClinPred

0.010

GERP RS

-5.0

Varity_R

0.051

gMVP

0.15

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over