rs16976354

Positions:

• chr15-55498216-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_130810.4(DNAAF4):​c.114C>A​(p.Asn38Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,613,942 control chromosomes in the GnomAD database, including 1,552 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.055 (786 hom., cov: 32)
  • Exomes 𝑓: 0.0055 (766 hom.)
• Consequence: DNAAF4 NM_130810.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0290

Genes affected

DNAAF4 (HGNC:21493): (dynein axonemal assembly factor 4) This gene encodes a tetratricopeptide repeat domain-containing protein. The encoded protein interacts with estrogen receptors and the heat shock proteins, Hsp70 and Hsp90. An homologous protein in rat has been shown to function in neuronal migration in the developing neocortex. A chromosomal translocation involving this gene is associated with a susceptibility to developmental dyslexia. Mutations in this gene are associated with deficits in reading and spelling. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the downstream cell cycle progression 1 (CCPG1) gene. [provided by RefSeq, Mar 2011]

DNAAF4-CCPG1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0011978745).
• BP6: Variant 15-55498216-G-T is Benign according to our data. Variant chr15-55498216-G-T is described in ClinVar as [Benign]. Clinvar id is 416510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.19 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAAF4	NM_130810.4	c.114C>A	p.Asn38Lys	missense_variant	2/10	ENST00000321149.7	NP_570722.2
DNAAF4-CCPG1	NR_037923.1	n.369C>A		non_coding_transcript_exon_variant	1/16
DNAAF4	NM_001033560.2	c.114C>A	p.Asn38Lys	missense_variant	2/9		NP_001028732.1
DNAAF4	NM_001033559.3	c.114C>A	p.Asn38Lys	missense_variant	2/9		NP_001028731.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAAF4	ENST00000321149.7	c.114C>A	p.Asn38Lys	missense_variant	2/10	1	NM_130810.4	ENSP00000323275	P1

Frequencies

GnomAD3 genomes AF: 0.0548 AC: 8345 AN: 152198 Hom.: 784 Cov.: 32

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0139

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: 0.000250

Gnomad OTH AF: 0.0363

GnomAD3 exomes AF: 0.0139 AC: 3492 AN: 250676 Hom.: 321 AF XY: 0.0100 AC XY: 1357 AN XY: 135602

Gnomad AFR exome AF: 0.197

Gnomad AMR exome AF: 0.00685

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000229

Gnomad OTH exome AF: 0.00573

GnomAD4 exome AF: 0.00548 AC: 8008 AN: 1461626 Hom.: 766 Cov.: 32 AF XY: 0.00465 AC XY: 3379 AN XY: 727112

Gnomad4 AFR exome AF: 0.204

Gnomad4 AMR exome AF: 0.00790

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000278

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000107

Gnomad4 OTH exome AF: 0.0109

GnomAD4 genome AF: 0.0549 AC: 8358 AN: 152316 Hom.: 786 Cov.: 32 AF XY: 0.0532 AC XY: 3961 AN XY: 74494

Gnomad4 AFR AF: 0.194

Gnomad4 AMR AF: 0.0140

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.0360

Alfa AF: 0.0125 Hom.: 263

Bravo AF: 0.0627

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.194 AC: 849

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0176 AC: 2132

Asia WGS AF: 0.00837 AC: 30 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000297

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 26, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	19
DANN	Benign	0.93
DEOGEN2	Benign	0.0019	.;.;T;T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.070	N
LIST_S2	Uncertain	0.86	D;D;D;.
MetaRNN	Benign	0.0012	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.13	N;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.30	T;T;T;T
Sift4G	Benign	0.58	T;T;T;T
Polyphen		0.82	P;B;B;B
Vest4		0.23
MutPred		0.20		Gain of ubiquitination at N38 (P = 0.0211);Gain of ubiquitination at N38 (P = 0.0211);Gain of ubiquitination at N38 (P = 0.0211);Gain of ubiquitination at N38 (P = 0.0211);
MPC		0.075
ClinPred		0.0020	T
GERP RS		-1.6
Varity_R		0.13
gMVP		0.17

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

Other links and lift over

dbSNP: rs16976354; hg19: chr15-55790414;