rs760482

chr22-38782696-A-Cchr22-38782696-A-Gchr22-38782696-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005740.3(DNAL4):c.36T>G(p.Asp12Glu) 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 1,460,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D12D) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DNAL4 NM_005740.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.248

Genes affected

DNAL4 (HGNC:2955): (dynein axonemal light chain 4) This gene encodes an axonemal dynein light chain which functions as a component of the outer dynein arms complex. This complex acts as the molecular motor that provides the force to move cilia in an ATP-dependent manner. The encoded protein is expressed in tissues with motile cilia or flagella and may be involved in the movement of sperm flagella. [provided by RefSeq, Dec 2014]

SUN2 (HGNC:14210): (Sad1 and UNC84 domain containing 2) SUN1 (MIM 607723) and SUN2 are inner nuclear membrane (INM) proteins that play a major role in nuclear-cytoplasmic connection by formation of a 'bridge' across the nuclear envelope, known as the LINC complex, via interaction with the conserved luminal KASH domain of nesprins (e.g., SYNE1; MIM 608441) located in the outer nuclear membrane (ONM). The LINC complex provides a direct connection between the nuclear lamina and the cytoskeleton, which contributes to nuclear positioning and cellular rigidity (summary by Haque et al., 2010 [PubMed 19933576]).[supplied by OMIM, Nov 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21263984).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAL4	NM_005740.3	c.36T>G	p.Asp12Glu	missense_variant	2/4	ENST00000216068.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAL4	ENST00000216068.9	c.36T>G	p.Asp12Glu	missense_variant	2/4	1	NM_005740.3	P1
DNAL4	ENST00000406199.3	c.36T>G	p.Asp12Glu	missense_variant	2/3	2
SUN2	ENST00000406622.5	c.-138+11372T>G		intron_variant		2		P2
DNAL4	ENST00000486019.1	n.82-3083T>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 249842 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135062

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460798 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 726718

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.0024	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	15
Dann	Uncertain	0.98
DEOGEN2	Benign	0.11	T;T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.41
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	0.000063	P;P;P
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.5	N;N
REVEL	Benign	0.21
Sift	Benign	0.28	T;T
Sift4G	Benign	0.57	T;T
Polyphen		0.17	B;.
Vest4		0.15
MutPred		0.17		Gain of methylation at K14 (P = 0.0942);Gain of methylation at K14 (P = 0.0942);
MVP		0.34
MPC		0.16
ClinPred		0.20	T
GERP RS		-2.4
Varity_R		0.39
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs760482; hg19: chr22-39178701; COSMIC: COSV53308910; COSMIC: COSV53308910;