22-38782696-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_005740.3(DNAL4):c.36T>C(p.Asp12=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.315 in 1,611,918 control chromosomes in the GnomAD database, including 84,416 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.33 (8650 hom., cov: 32)
  • Exomes 𝑓: 0.31 (75766 hom.)
• Consequence: DNAL4 NM_005740.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 22-38782696-A-G is Benign according to our data. Variant chr22-38782696-A-G is described in ClinVar as [Benign]. Clinvar id is 402791.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.248 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.657 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAL4	NM_005740.3	c.36T>C	p.Asp12=	synonymous_variant	2/4	ENST00000216068.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAL4	ENST00000216068.9	c.36T>C	p.Asp12=	synonymous_variant	2/4	1	NM_005740.3	P1
DNAL4	ENST00000406199.3	c.36T>C	p.Asp12=	synonymous_variant	2/3	2
SUN2	ENST00000406622.5	c.-138+11372T>C		intron_variant		2		P2
DNAL4	ENST00000486019.1	n.82-3083T>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.327 AC: 49754 AN: 151994 Hom.: 8655 Cov.: 32

Gnomad AFR AF: 0.375

Gnomad AMI AF: 0.335

Gnomad AMR AF: 0.246

Gnomad ASJ AF: 0.268

Gnomad EAS AF: 0.676

Gnomad SAS AF: 0.393

Gnomad FIN AF: 0.223

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.306

Gnomad OTH AF: 0.300

GnomAD3 exomes AF: 0.322 AC: 80391 AN: 249842 Hom.: 14776 AF XY: 0.327 AC XY: 44151 AN XY: 135062

Gnomad AFR exome AF: 0.375

Gnomad AMR exome AF: 0.187

Gnomad ASJ exome AF: 0.266

Gnomad EAS exome AF: 0.687

Gnomad SAS exome AF: 0.387

Gnomad FIN exome AF: 0.230

Gnomad NFE exome AF: 0.303

Gnomad OTH exome AF: 0.299

GnomAD4 exome AF: 0.313 AC: 457437 AN: 1459806 Hom.: 75766 Cov.: 35 AF XY: 0.316 AC XY: 229226 AN XY: 726264

Gnomad4 AFR exome AF: 0.380

Gnomad4 AMR exome AF: 0.193

Gnomad4 ASJ exome AF: 0.264

Gnomad4 EAS exome AF: 0.664

Gnomad4 SAS exome AF: 0.391

Gnomad4 FIN exome AF: 0.236

Gnomad4 NFE exome AF: 0.302

Gnomad4 OTH exome AF: 0.321

GnomAD4 genome AF: 0.327 AC: 49764 AN: 152112 Hom.: 8650 Cov.: 32 AF XY: 0.323 AC XY: 24007 AN XY: 74390

Gnomad4 AFR AF: 0.374

Gnomad4 AMR AF: 0.246

Gnomad4 ASJ AF: 0.268

Gnomad4 EAS AF: 0.676

Gnomad4 SAS AF: 0.392

Gnomad4 FIN AF: 0.223

Gnomad4 NFE AF: 0.306

Gnomad4 OTH AF: 0.299

Alfa AF: 0.314 Hom.: 15668

Bravo AF: 0.329

Asia WGS AF: 0.460 AC: 1596 AN: 3478

EpiCase AF: 0.307

EpiControl AF: 0.300

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
Cadd	Benign	7.3
Dann	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: COSV53308873; COSMIC: COSV53308873;