rs1284785470

Variant names:

• chr5-141573843-C-A
• rs1284785470
• NM_005219.5:c.2007G>T
• DIAPH1 p.Leu669Phe

Your query was ambiguous. Multiple possible variants found:

• chr5-141573843-C-A
• chr5-141573843-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4 BP6

The NM_005219.5(DIAPH1):​c.2007G>T​(p.Leu669Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000132 in 1,513,304 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L669L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000072 (0 hom., cov: 24)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: DIAPH1 NM_005219.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -3.33
• Publications: 2 publications found

Genes affected

DIAPH1 (HGNC:2876): (diaphanous related formin 1) This gene is a homolog of the Drosophila diaphanous gene, and has been linked to autosomal dominant, fully penetrant, nonsyndromic sensorineural progressive low-frequency hearing loss. Actin polymerization involves proteins known to interact with diaphanous protein in Drosophila and mouse. It has therefore been speculated that this gene may have a role in the regulation of actin polymerization in hair cells of the inner ear. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

DIAPH1 Gene-Disease associations (from GenCC):

• DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• progressive microcephaly-seizures-cortical blindness-developmental delay syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• autosomal dominant nonsyndromic hearing loss 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27775455).
• BP6: Variant 5-141573843-C-A is Benign according to our data. Variant chr5-141573843-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 689603.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005219.5. 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
	DIAPH1	NM_005219.5	MANE Select	c.2007G>T	p.Leu669Phe	missense	Exon 16 of 28	NP_005210.3
	DIAPH1	NM_001079812.3		c.1980G>T	p.Leu660Phe	missense	Exon 15 of 27	NP_001073280.1	O60610-3
	DIAPH1	NM_001314007.2		c.2007G>T	p.Leu669Phe	missense	Exon 16 of 29	NP_001300936.1	A0A2R8Y5N1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIAPH1	ENST00000389054.8	TSL:5 MANE Select	c.2007G>T	p.Leu669Phe	missense	Exon 16 of 28	ENSP00000373706.4	O60610-1
	DIAPH1	ENST00000518047.5	TSL:5	c.1980G>T	p.Leu660Phe	missense	Exon 15 of 27	ENSP00000428268.2	O60610-3
	DIAPH1	ENST00000647433.1		c.2007G>T	p.Leu669Phe	missense	Exon 16 of 29	ENSP00000494675.1	A0A2R8Y5N1

Frequencies

GnomAD3 genomes AF: 0.00000719 AC: 1 AN: 139068 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000212

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000144 AC: 2 AN: 138434 AF XY: 0.0000283

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000178

Gnomad EAS exome AF: 0.0000828

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.28e-7 AC: 1 AN: 1374122 Hom.: 0 Cov.: 36 AF XY: 0.00000149 AC XY: 1 AN XY: 673002

African (AFR) AF: 0.00 AC: 0 AN: 31960

American (AMR) AF: 0.00 AC: 0 AN: 34590

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22386

East Asian (EAS) AF: 0.0000273 AC: 1 AN: 36656

South Asian (SAS) AF: 0.00 AC: 0 AN: 72700

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48278

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5534

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1064964

Other (OTH) AF: 0.00 AC: 0 AN: 57054

GnomAD4 genome AF: 0.00000718 AC: 1 AN: 139182 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 66834

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

African (AFR) AF: 0.00 AC: 0 AN: 36510

American (AMR) AF: 0.00 AC: 0 AN: 13230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3400

East Asian (EAS) AF: 0.000212 AC: 1 AN: 4710

South Asian (SAS) AF: 0.00 AC: 0 AN: 4396

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 242

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65314

Other (OTH) AF: 0.00 AC: 0 AN: 1886

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Autosomal dominant nonsyndromic hearing loss 1 (1)
-	1	-	Autosomal dominant nonsyndromic hearing loss 1;C5567650:Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	10
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.39	T
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	2.0	M
PhyloP100		-3.3
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.53	N
REVEL	Uncertain	0.31
Sift	Benign	0.044	D
Sift4G	Benign	0.20	T
Varity_R		0.062
gMVP		0.044
Mutation Taster		=49/51	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1284785470; hg19: chr5-140953410;