2-195897767-TAAAAAAAA-TAAAAA

Variant names:

• chr2-195897767-TAAA-T
• rs61502519
• NM_018897.3:c.4549-5_4549-3delTTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_018897.3(DNAH7):​c.4549-5_4549-3delTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00238 in 1,138,928 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000024 (0 hom., cov: 16)
  • Exomes 𝑓: 0.0027 (0 hom.)
• Consequence: DNAH7 NM_018897.3 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.03
• Publications: 1 publications found

Genes affected

DNAH7 (HGNC:18661): (dynein axonemal heavy chain 7) DNAH7 is a component of the inner dynein arm of ciliary axonemes (Zhang et al., 2002 [PubMed 11877439]).[supplied by OMIM, Mar 2008]

DNAH7 Gene-Disease associations (from GenCC):

• ciliary dyskinesia, primary, 50

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• male infertility with azoospermia or oligozoospermia due to single gene mutation

  Inheritance: AR Classification: LIMITED Submitted by: King Faisal Specialist Hospital and Research Center

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Variant has high frequency in the AFR (0.00555) population. However there is too low homozygotes in high coverage region: (expected more than 1, got 0).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018897.3. 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
	DNAH7	NM_018897.3	MANE Select	c.4549-5_4549-3delTTT		splice_region intron	N/A	NP_061720.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH7	ENST00000312428.11	TSL:1 MANE Select	c.4549-5_4549-3delTTT		splice_region intron	N/A	ENSP00000311273.6
	DNAH7	ENST00000475293.1	TSL:1	n.5482-5_5482-3delTTT		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000240 AC: 3 AN: 124976 Hom.: 0 Cov.: 16

Gnomad AFR AF: 0.0000271

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: 0.000305

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00445 AC: 414 AN: 93048 AF XY: 0.00465

Gnomad AFR exome AF: 0.00770

Gnomad AMR exome AF: 0.00525

Gnomad ASJ exome AF: 0.00497

Gnomad EAS exome AF: 0.00332

Gnomad FIN exome AF: 0.00162

Gnomad NFE exome AF: 0.00396

Gnomad OTH exome AF: 0.00840

GnomAD4 exome AF: 0.00266 AC: 2702 AN: 1013942 Hom.: 0 AF XY: 0.00259 AC XY: 1329 AN XY: 512452

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00641 AC: 142 AN: 22170

American (AMR) AF: 0.00400 AC: 93 AN: 23262

Ashkenazi Jewish (ASJ) AF: 0.00360 AC: 69 AN: 19192

East Asian (EAS) AF: 0.00115 AC: 38 AN: 33100

South Asian (SAS) AF: 0.00400 AC: 228 AN: 57070

European-Finnish (FIN) AF: 0.00159 AC: 64 AN: 40354

Middle Eastern (MID) AF: 0.00370 AC: 16 AN: 4326

European-Non Finnish (NFE) AF: 0.00250 AC: 1927 AN: 770630

Other (OTH) AF: 0.00285 AC: 125 AN: 43838

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000240 AC: 3 AN: 124986 Hom.: 0 Cov.: 16 AF XY: 0.00 AC XY: 0 AN XY: 59862

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000271 AC: 1 AN: 36916

American (AMR) AF: 0.00 AC: 0 AN: 12006

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2982

East Asian (EAS) AF: 0.00 AC: 0 AN: 3956

South Asian (SAS) AF: 0.00 AC: 0 AN: 3712

European-Finnish (FIN) AF: 0.000305 AC: 2 AN: 6568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 214

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 56230

Other (OTH) AF: 0.00 AC: 0 AN: 1690

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0160444), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.0
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs61502519; hg19: chr2-196762491; COSMIC: COSV108154155;