chr14-73654878-C-T

Variant names:

• chr14-73654878-C-T
• rs948104206
• NM_031427.4:c.35C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_031427.4(DNAL1):​c.35C>T​(p.Ala12Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,537,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A12T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: DNAL1 NM_031427.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.50
• Publications: 0 publications found

Genes affected

DNAL1 (HGNC:23247): (dynein axonemal light chain 1) 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. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Jan 2011]

DNAL1 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 16

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19695517).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031427.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAL1	NM_031427.4	MANE Select	c.35C>T	p.Ala12Val	missense	Exon 2 of 8	NP_113615.2
	DNAL1	NM_001201366.2		c.-83C>T		5_prime_UTR	Exon 3 of 9	NP_001188295.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAL1	ENST00000553645.7	TSL:1 MANE Select	c.35C>T	p.Ala12Val	missense	Exon 2 of 8	ENSP00000452037.1
	DNAL1	ENST00000554871.5	TSL:1	c.-83C>T		5_prime_UTR	Exon 3 of 9	ENSP00000451834.1
	DNAL1	ENST00000893991.1		c.35C>T	p.Ala12Val	missense	Exon 2 of 7	ENSP00000564050.1

Frequencies

GnomAD3 genomes AF: 0.00000665 AC: 1 AN: 150290 Hom.: 0 Cov.: 32

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 148612 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 19 AN: 1387518 Hom.: 0 Cov.: 33 AF XY: 0.0000132 AC XY: 9 AN XY: 683980

African (AFR) AF: 0.00 AC: 0 AN: 30830

American (AMR) AF: 0.00 AC: 0 AN: 33502

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24830

East Asian (EAS) AF: 0.00 AC: 0 AN: 35602

South Asian (SAS) AF: 0.00 AC: 0 AN: 76078

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48098

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5582

European-Non Finnish (NFE) AF: 0.0000177 AC: 19 AN: 1075386

Other (OTH) AF: 0.00 AC: 0 AN: 57610

GnomAD4 genome AF: 0.00000665 AC: 1 AN: 150290 Hom.: 0 Cov.: 32 AF XY: 0.0000137 AC XY: 1 AN XY: 73158

African (AFR) AF: 0.00 AC: 0 AN: 40752

American (AMR) AF: 0.00 AC: 0 AN: 15074

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4774

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10034

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67740

Other (OTH) AF: 0.00 AC: 0 AN: 2066

Alfa AF: 0.0000843 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Primary ciliary dyskinesia 16 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.049	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.066
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.7	L
PhyloP100		3.5
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.16
Sift	Benign	0.13	T
Sift4G	Benign	0.091	T
Polyphen		0.0010	B
Vest4		0.24
MutPred		0.42		Gain of catalytic residue at L11 (P = 0.0173)
MVP		0.50
MPC		0.35
ClinPred		0.79	D
GERP RS		4.8
Varity_R		0.16
gMVP		0.29
Mutation Taster		=271/29	polymorphism

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

Other links and lift over

dbSNP: rs948104206; hg19: chr14-74121581; COSMIC: COSV60726745; COSMIC: COSV60726745;