rs2277617

Variant names:

• chr17-44899705-T-G
• rs2277617
• ENST00000577339.5:c.-10+175T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000577339.5(DNAAF19):​c.-10+175T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.255 in 152,168 control chromosomes in the GnomAD database, including 5,301 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5293 hom., cov: 31)
  • Exomes 𝑓: 0.38 (8 hom.)
• Consequence: DNAAF19 ENST00000577339.5 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.431
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 17-44899705-T-G is Benign according to our data. Variant chr17-44899705-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 369146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.343 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000577339.5. 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.-164T>G		upstream_gene	N/A	NP_998772.1	Q8IW40-1
	DNAAF19	NM_001258395.2		c.-134T>G		upstream_gene	N/A	NP_001245324.1	Q8IW40-1
	DNAAF19	NM_001258396.2		c.-148T>G		upstream_gene	N/A	NP_001245325.1	Q8IW40-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF19	ENST00000577339.5	TSL:4	c.-10+175T>G		intron	N/A	ENSP00000462450.1	J3KSE5
	DNAAF19	ENST00000417826.3	TSL:1 MANE Select	c.-164T>G		upstream_gene	N/A	ENSP00000391692.2	Q8IW40-1
	EFTUD2	ENST00000880573.1		c.-341A>C		upstream_gene	N/A	ENSP00000550632.1

Frequencies

GnomAD3 genomes AF: 0.255 AC: 38702 AN: 151948 Hom.: 5278 Cov.: 31

Gnomad AFR AF: 0.347

Gnomad AMI AF: 0.336

Gnomad AMR AF: 0.212

Gnomad ASJ AF: 0.204

Gnomad EAS AF: 0.221

Gnomad SAS AF: 0.275

Gnomad FIN AF: 0.182

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.224

Gnomad OTH AF: 0.205

GnomAD4 exome AF: 0.382 AC: 39 AN: 102 Hom.: 8 Cov.: 0 AF XY: 0.414 AC XY: 29 AN XY: 70

African (AFR) AF: 0.375 AC: 3 AN: 8

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.500 AC: 2 AN: 4

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.397 AC: 31 AN: 78

Other (OTH) AF: 0.500 AC: 3 AN: 6

GnomAD4 genome AF: 0.255 AC: 38754 AN: 152066 Hom.: 5293 Cov.: 31 AF XY: 0.252 AC XY: 18709 AN XY: 74346

African (AFR) AF: 0.347 AC: 14403 AN: 41452

American (AMR) AF: 0.212 AC: 3244 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.204 AC: 709 AN: 3468

East Asian (EAS) AF: 0.221 AC: 1140 AN: 5164

South Asian (SAS) AF: 0.274 AC: 1321 AN: 4822

European-Finnish (FIN) AF: 0.182 AC: 1926 AN: 10588

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.224 AC: 15249 AN: 67992

Other (OTH) AF: 0.202 AC: 425 AN: 2102

Alfa AF: 0.239 Hom.: 740

Bravo AF: 0.265

Asia WGS AF: 0.262 AC: 910 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.4
DANN	Benign	0.74
PhyloP100		-0.43
PromoterAI		0.031	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs2277617; hg19: chr17-42977073;