NM_213607.3:c.-45G>A

Variant names:

• chr17-44899824-G-A
• rs2277616
• NM_213607.3:c.-45G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_213607.3(DNAAF19):​c.-45G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0947 in 152,588 control chromosomes in the GnomAD database, including 756 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.095 (751 hom., cov: 31)
  • Exomes 𝑓: 0.12 (5 hom.)
• Consequence: DNAAF19 NM_213607.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.229
• Publications: 15 publications found

Genes affected

DNAAF19 (HGNC:32700): (coiled-coil domain containing 103) Enables protein homodimerization activity. Involved in axonemal dynein complex assembly; cilium movement; and determination of left/right symmetry. Predicted to be located in axoneme. Predicted to be part of outer dynein arm. Implicated in primary ciliary dyskinesia 17. [provided by Alliance of Genome Resources, Apr 2022]

EFTUD2 (HGNC:30858): (elongation factor Tu GTP binding domain containing 2) This gene encodes a GTPase which is a component of the spliceosome complex which processes precursor mRNAs to produce mature mRNAs. Mutations in this gene are associated with mandibulofacial dysostosis with microcephaly. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

EFTUD2 Gene-Disease associations (from GenCC):

• mandibulofacial dysostosis-microcephaly syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 17-44899824-G-A is Benign according to our data. Variant chr17-44899824-G-A is described in ClinVar as Benign. ClinVar VariationId is 323580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_213607.3. 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
	DNAAF19	NM_213607.3	MANE Select	c.-45G>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 4	NP_998772.1	Q8IW40-1
	DNAAF19	NM_213607.3	MANE Select	c.-45G>A		5_prime_UTR	Exon 1 of 4	NP_998772.1	Q8IW40-1
	DNAAF19	NM_001258395.2		c.-15G>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 4	NP_001245324.1	Q8IW40-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF19	ENST00000417826.3	TSL:1 MANE Select	c.-45G>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 4	ENSP00000391692.2	Q8IW40-1
	DNAAF19	ENST00000417826.3	TSL:1 MANE Select	c.-45G>A		5_prime_UTR	Exon 1 of 4	ENSP00000391692.2	Q8IW40-1
	DNAAF19	ENST00000410006.6	TSL:2	c.-15G>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 4	ENSP00000387252.1	Q8IW40-1

Frequencies

GnomAD3 genomes AF: 0.0947 AC: 14406 AN: 152120 Hom.: 753 Cov.: 31

Gnomad AFR AF: 0.0512

Gnomad AMI AF: 0.111

Gnomad AMR AF: 0.0998

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.0906

Gnomad SAS AF: 0.115

Gnomad FIN AF: 0.0854

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.115

Gnomad OTH AF: 0.120

GnomAD4 exome AF: 0.123 AC: 43 AN: 350 Hom.: 5 Cov.: 0 AF XY: 0.130 AC XY: 34 AN XY: 262

African (AFR) AF: 0.00 AC: 0 AN: 6

American (AMR) AF: 0.250 AC: 1 AN: 4

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 1 AN: 4

East Asian (EAS) AF: 0.400 AC: 4 AN: 10

South Asian (SAS) AF: 0.125 AC: 1 AN: 8

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.118 AC: 33 AN: 280

Other (OTH) AF: 0.150 AC: 3 AN: 20

GnomAD4 genome AF: 0.0946 AC: 14406 AN: 152238 Hom.: 751 Cov.: 31 AF XY: 0.0929 AC XY: 6917 AN XY: 74426

African (AFR) AF: 0.0511 AC: 2125 AN: 41550

American (AMR) AF: 0.0996 AC: 1523 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 592 AN: 3472

East Asian (EAS) AF: 0.0906 AC: 469 AN: 5174

South Asian (SAS) AF: 0.115 AC: 556 AN: 4830

European-Finnish (FIN) AF: 0.0854 AC: 905 AN: 10598

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.115 AC: 7809 AN: 68006

Other (OTH) AF: 0.119 AC: 251 AN: 2112

Alfa AF: 0.114 Hom.: 1678

Bravo AF: 0.0941

Asia WGS AF: 0.100 AC: 347 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Primary ciliary dyskinesia 17 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	11
DANN	Benign	0.75
PhyloP100		0.23
PromoterAI		-0.010	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.29		Position offset: 5

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

Other links and lift over

dbSNP: rs2277616; hg19: chr17-42977192;