NM_178452.6:c.-128G>C

Variant names:

• chr16-84145313-G-C
• rs140245131
• NM_178452.6:c.-128G>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_178452.6(DNAAF1):​c.-128G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0167 in 1,486,218 control chromosomes in the GnomAD database, including 261 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (24 hom., cov: 32)
  • Exomes 𝑓: 0.017 (237 hom.)
• Consequence: DNAAF1 NM_178452.6 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.639
• Publications: 2 publications found

Genes affected

DNAAF1 (HGNC:30539): (dynein axonemal assembly factor 1) The protein encoded by this gene is cilium-specific and is required for the stability of the ciliary architecture. It is involved in the regulation of microtubule-based cilia and actin-based brush border microvilli. Mutations in this gene are associated with primary ciliary dyskinesia-13. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

HSDL1 (HGNC:16475): (hydroxysteroid dehydrogenase like 1) Predicted to enable oxidoreductase activity. Located in intermediate filament cytoskeleton and mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0139 (2122/152252) while in subpopulation NFE AF = 0.0198 (1348/67996). AF 95% confidence interval is 0.0189. There are 24 homozygotes in GnomAd4. There are 1036 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 24 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178452.6. 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
	DNAAF1	NM_178452.6	MANE Select	c.-128G>C		5_prime_UTR	Exon 1 of 12	NP_848547.4
	HSDL1	NM_031463.5	MANE Select	c.-302C>G		upstream_gene	N/A	NP_113651.4
	HSDL1	NM_001146051.2		c.-302C>G		upstream_gene	N/A	NP_001139523.1	Q3SXM5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF1	ENST00000378553.10	TSL:1 MANE Select	c.-128G>C		5_prime_UTR	Exon 1 of 12	ENSP00000367815.5	Q8NEP3-1
	DNAAF1	ENST00000567918.5	TSL:1	n.-128G>C		non_coding_transcript_exon	Exon 1 of 7	ENSP00000455154.1	H3BP51
	DNAAF1	ENST00000567918.5	TSL:1	n.-128G>C		5_prime_UTR	Exon 1 of 7	ENSP00000455154.1	H3BP51

Frequencies

GnomAD3 genomes AF: 0.0140 AC: 2123 AN: 152134 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.00328

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.0143

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0223

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0198

Gnomad OTH AF: 0.0196

GnomAD4 exome AF: 0.0170 AC: 22652 AN: 1333966 Hom.: 237 Cov.: 22 AF XY: 0.0166 AC XY: 10964 AN XY: 658696

African (AFR) AF: 0.00318 AC: 97 AN: 30458

American (AMR) AF: 0.0105 AC: 370 AN: 35282

Ashkenazi Jewish (ASJ) AF: 0.0117 AC: 289 AN: 24632

East Asian (EAS) AF: 0.00 AC: 0 AN: 35218

South Asian (SAS) AF: 0.00423 AC: 327 AN: 77310

European-Finnish (FIN) AF: 0.0249 AC: 867 AN: 34878

Middle Eastern (MID) AF: 0.0102 AC: 44 AN: 4314

European-Non Finnish (NFE) AF: 0.0191 AC: 19796 AN: 1035936

Other (OTH) AF: 0.0154 AC: 862 AN: 55938

GnomAD4 genome AF: 0.0139 AC: 2122 AN: 152252 Hom.: 24 Cov.: 32 AF XY: 0.0139 AC XY: 1036 AN XY: 74462

African (AFR) AF: 0.00327 AC: 136 AN: 41556

American (AMR) AF: 0.0143 AC: 219 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00922 AC: 32 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4830

European-Finnish (FIN) AF: 0.0223 AC: 237 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0198 AC: 1348 AN: 67996

Other (OTH) AF: 0.0194 AC: 41 AN: 2114

Alfa AF: 0.0180 Hom.: 4

Bravo AF: 0.0125

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	Primary ciliary dyskinesia 13 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.1
DANN	Benign	0.36
PhyloP100		-0.64
PromoterAI		0.10	Neutral
Mutation Taster		=300/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs140245131; hg19: chr16-84178918;