1-66834027-A-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6_Moderate

The NM_024763.5(DNAI4):ā€‹c.1855T>Gā€‹(p.Ser619Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000808 in 1,609,306 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000082 ( 0 hom. )

Consequence

DNAI4
NM_024763.5 missense

Scores

1
18

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.59
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]

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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=0.07664275).
BP6
Variant 1-66834027-A-C is Benign according to our data. Variant chr1-66834027-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 2556434.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DNAI4NM_024763.5 linkuse as main transcriptc.1855T>G p.Ser619Ala missense_variant 12/17 ENST00000371026.8 NP_079039.4 Q5VTH9-1A0AVI9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DNAI4ENST00000371026.8 linkuse as main transcriptc.1855T>G p.Ser619Ala missense_variant 12/171 NM_024763.5 ENSP00000360065.3 Q5VTH9-1
DNAI4ENST00000464352.6 linkuse as main transcriptc.1153T>G p.Ser385Ala missense_variant 8/122 ENSP00000433682.1 H0YDI6
DNAI4ENST00000491297.6 linkuse as main transcriptn.*1797T>G non_coding_transcript_exon_variant 9/142 ENSP00000435836.1 H0YEH4
DNAI4ENST00000491297.6 linkuse as main transcriptn.*1797T>G 3_prime_UTR_variant 9/142 ENSP00000435836.1 H0YEH4

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152090
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000243
AC:
6
AN:
246496
Hom.:
0
AF XY:
0.0000150
AC XY:
2
AN XY:
133220
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000206
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000823
AC:
12
AN:
1457216
Hom.:
0
Cov.:
31
AF XY:
0.00000828
AC XY:
6
AN XY:
724736
show subpopulations
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:
0.0000942
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.0000498
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152090
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74252
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsJun 05, 2023This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.065
BayesDel_addAF
Benign
-0.29
T
BayesDel_noAF
Benign
-0.38
CADD
Benign
15
DANN
Benign
0.72
DEOGEN2
Benign
0.0026
T;.
Eigen
Benign
-1.4
Eigen_PC
Benign
-1.2
FATHMM_MKL
Uncertain
0.81
D
LIST_S2
Benign
0.38
T;T
M_CAP
Benign
0.025
D
MetaRNN
Benign
0.077
T;T
MetaSVM
Benign
-0.91
T
MutationAssessor
Benign
0.20
N;.
PrimateAI
Benign
0.45
T
PROVEAN
Benign
-1.1
N;N
REVEL
Benign
0.22
Sift
Benign
0.29
T;T
Sift4G
Benign
0.13
T;T
Polyphen
0.0
B;.
Vest4
0.24
MutPred
0.43
Loss of sheet (P = 0.1158);.;
MVP
0.42
MPC
0.081
ClinPred
0.037
T
GERP RS
-1.8
Varity_R
0.072
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

LitVar

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

Other links and lift over

dbSNP: rs769220230; hg19: chr1-67299710; API