5-141527619-A-C

Variant names:

• chr5-141527619-A-C
• rs143763573
• NM_005219.5:c.3227T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005219.5(DIAPH1):​c.3227T>G​(p.Phe1076Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000769 in 1,612,698 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F1076I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0033 (4 hom., cov: 30)
  • Exomes 𝑓: 0.00051 (7 hom.)
• Consequence: DIAPH1 NM_005219.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 7.25
• Publications: 5 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009181917).
• BP6: Variant 5-141527619-A-C is Benign according to our data. Variant chr5-141527619-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226565.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00326 (495/151612) while in subpopulation AFR AF = 0.0111 (458/41250). AF 95% confidence interval is 0.0103. There are 4 homozygotes in GnomAd4. There are 244 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

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.3227T>G	p.Phe1076Cys	missense	Exon 24 of 28	NP_005210.3
	DIAPH1	NM_001079812.3		c.3200T>G	p.Phe1067Cys	missense	Exon 23 of 27	NP_001073280.1	O60610-3
	DIAPH1	NM_001314007.2		c.3227T>G	p.Phe1076Cys	missense	Exon 24 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.3227T>G	p.Phe1076Cys	missense	Exon 24 of 28	ENSP00000373706.4	O60610-1
	DIAPH1	ENST00000518047.5	TSL:5	c.3200T>G	p.Phe1067Cys	missense	Exon 23 of 27	ENSP00000428268.2	O60610-3
	DIAPH1	ENST00000647433.1		c.3227T>G	p.Phe1076Cys	missense	Exon 24 of 29	ENSP00000494675.1	A0A2R8Y5N1

Frequencies

GnomAD3 genomes AF: 0.00325 AC: 493 AN: 151502 Hom.: 4 Cov.: 30

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000987

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000236

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000898 AC: 224 AN: 249348 AF XY: 0.000710

Gnomad AFR exome AF: 0.0117

Gnomad AMR exome AF: 0.000522

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000661

GnomAD4 exome AF: 0.000510 AC: 745 AN: 1461086 Hom.: 7 Cov.: 34 AF XY: 0.000477 AC XY: 347 AN XY: 726824

African (AFR) AF: 0.0156 AC: 523 AN: 33444

American (AMR) AF: 0.000604 AC: 27 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39610

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86202

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53336

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5762

European-Non Finnish (NFE) AF: 0.0000819 AC: 91 AN: 1111580

Other (OTH) AF: 0.00126 AC: 76 AN: 60344

GnomAD4 genome AF: 0.00326 AC: 495 AN: 151612 Hom.: 4 Cov.: 30 AF XY: 0.00329 AC XY: 244 AN XY: 74082

African (AFR) AF: 0.0111 AC: 458 AN: 41250

American (AMR) AF: 0.000985 AC: 15 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10474

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000236 AC: 16 AN: 67926

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00154 Hom.: 4

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0101 AC: 37

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00103 AC: 125

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	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	Pathogenic	0.60
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.24	T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0092	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.2
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.024	D
Sift4G	Benign	0.065	T
Polyphen		1.0	D
Vest4		0.70
MVP		0.54
MPC		1.8
ClinPred		0.075	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56
gMVP		0.53
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs143763573; hg19: chr5-140907186; COSMIC: COSV107276540; COSMIC: COSV107276540;