2-195738000-G-A

Position:

• chr2-195738000-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000312428.11(DNAH7):​c.11996C>T​(p.Ala3999Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,794 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DNAH7 ENST00000312428.11 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.94

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH7	NM_018897.3	c.11996C>T	p.Ala3999Val	missense_variant	65/65	ENST00000312428.11	NP_061720.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH7	ENST00000312428.11	c.11996C>T	p.Ala3999Val	missense_variant	65/65	1	NM_018897.3	ENSP00000311273	P1
DNAH7	ENST00000409063.5	c.1445C>T	p.Ala482Val	missense_variant	10/10	1		ENSP00000386912
DNAH7	ENST00000438565.1	c.*127C>T		3_prime_UTR_variant	3/3	3		ENSP00000409732
DNAH7	ENST00000484183.1	n.494C>T		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461794 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727202

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 25, 2024

The c.11996C>T (p.A3999V) alteration is located in exon 65 (coding exon 65) of the DNAH7 gene. This alteration results from a C to T substitution at nucleotide position 11996, causing the alanine (A) at amino acid position 3999 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.56
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.038	.;T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.71	D;D
MetaSVM	Benign	-0.63	T
MutationAssessor	Pathogenic	3.1	.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Benign	0.24
Sift	Benign	0.47	T;T
Sift4G	Benign	0.38	T;.
Polyphen		0.93	.;P
Vest4		0.65
MutPred		0.54		.;Gain of sheet (P = 0.1208);
MVP		0.50
MPC		0.20
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.37
gMVP		0.64

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: rs1692744405; hg19: chr2-196602724; COSMIC: COSV100414094; COSMIC: COSV100414094;